Systemic sclerosis, a form of scleroderma, is a rare disease that causes the hardening of the body’s connective tissue.
Gloria Blecha, the Director of Community Engagement at the <a href="https://srfcure.org/">Scleroderma Research Foundation</a> (SRF), explains that the autoimmune disorder is characterized by systemic inflammation which often presents with “puffy” hands although other areas of the body can be affected. Ultimately, the inflammation triggers a secondary process that is the production of collagen which is a core material of scar tissue. This secondary process, which is called fibrosis, is often uncoupled to the initial inflammation. In the most serious cases, fibrosis can result in irreversible damage to specific organs such as the heart, lungs, and/or digestive system. In other situations, there can be loss of function of the hands.
Scleroderma is best thought of as a single disease but in actuality can be complex and have a variable course such that some patients are affected early with aggressive changes while others have fewer symptoms and the disease progresses slowly. Treatment depends on the symptoms that are present and the organs that are affected and because scleroderma is a heterogeneous disease, meaning it presents differently in each patient, treatments that work for one patient may not be effective for another.
<img loading="lazy" decoding="async" class="aligncenter size-larger wp-image-29049" src="http://35.88.189.111/wp-content/uploads/2021/07/Gloria-headshot-587x880.jpg" alt="" width="587" height="880" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/07/Gloria-headshot-587x880.jpg 587w, https://blogcms.23andme.com/wp-content/uploads/2021/07/Gloria-headshot-200x300.jpg 200w, https://blogcms.23andme.com/wp-content/uploads/2021/07/Gloria-headshot-768x1151.jpg 768w, https://blogcms.23andme.com/wp-content/uploads/2021/07/Gloria-headshot-684x1024.jpg 684w, https://blogcms.23andme.com/wp-content/uploads/2021/07/Gloria-headshot-788x1180.jpg 788w, https://blogcms.23andme.com/wp-content/uploads/2021/07/Gloria-headshot.jpg 1367w" sizes="auto, (max-width: 587px) 100vw, 587px" />
Scleroderma affects an estimated <a href="https://worldsclerofound.org/what-is-ss/">2.5 million people</a> globally, and most of them — about 80 percent — are women of between 16 and 45. Although there are some treatments for this progressively debilitating autoimmune disease, there currently is no cure. But there is promising research, including work supported by the Scleroderma Research Foundation and 23andMe. 23andMe is currently recruiting for two rare disease studies, <a href="https://www.23andme.com/idiopathic-pulmonary-fibrosis/">idiopathic pulmonary fibrosis (IPF)</a>, a chronic progressive lung disease, and 23andMe launched the <a href="https://www.23andme.com/systemic-sclerosis-study/">Systemic Sclerosis Research Study</a> last year. The study on systemic sclerosis aims to gather new genetic insights that could lead to new treatments for the condition.
23andMe’s unique research model offers a different approach to <a href="https://blog.23andme.com/23andme-research/new-way-to-study-rare-disease/">studying rare diseases</a>. By leveraging this approach, 23andMe hopes to help study systemic sclerosis at a scale that has not been possible in the past. That’s in part why 23andMe is currently working with the Scleroderma Research Foundation to help get the word out about our study. The foundation is a nonprofit that invests in scleroderma research conducted worldwide.
We sat down, virtually, with Gloria to talk a bit about the condition, the need for research, and the challenges of studying a rare disease like scleroderma.
<h6>In a way, the foundation’s origin story is sort of emblematic of rare diseases in general. Can you talk a bit about that?</h6>
Getting a diagnosis for any serious disease can be traumatic, but in rare diseases like scleroderma, there is this added issue of the unknown. For patients with a rare disease, there often isn’t a lot of information out there. The foundation was founded in 1987 by Sharon Monsky, three years after being diagnosed with scleroderma. She was shocked at how little was understood about the disease and the lack of efforts being made to find a cure. Using her business acumen and expertise, she took it upon herself to bring national attention to this disease and was soon privately funding research at two centers on the east and west coasts. Today we are the largest nonprofit supporting scleroderma research in the U.S. and Sharon’s collaborative approach and innovative spirit continue to drive the SRF’s mission to this day.  (Sharon <a href="https://www.nytimes.com/2002/05/17/us/sharon-monsky-48-leader-in-fight-against-rare-illness.html">passed away</a> in 2002.)
<h6>Last month, June, was Scleroderma Awareness Month, and the foundation spearheaded a social media campaign called ‘#SayScleroderma.’ What was the goal of that campaign?</h6>
Our primary goal is to fund research and find a cure for scleroderma and we additionally raise awareness and provide education for people living with this disease. We launched the #SaySCLERODERMA campaign because not enough people know what scleroderma is or does and this lack of awareness can delay diagnosis. 
All month long we shared stories of brave scleroderma warriors and their supporters. We created a toolkit using the hashtag #SaySCLERODERMA and challenged others to spread awareness by saying the word or posting videos explaining what this disease means to them on social media. Our goal is to bring a global spotlight on the word scleroderma and bring knowledge of the disease forward so that more people know what it is and what it does. 
<h6>What is encouraging that you are seeing in the way of research and treatments?</h6>
Although the search for more targeted disease-modifying therapy is ongoing, what is encouraging is that there are now treatments available for some of the symptoms of scleroderma. For example, people suffering from something called Raynaud’s phenomenon, which affects circulation to the fingers and toes, have calcium channel blockers and alpha-blockers that can help with symptoms. But as I mentioned earlier, the more awareness there is the more likely it is that people will be diagnosed early which can improve their response to treatment. 
<h6>Late last year 23andMe launched our Systemic Sclerosis Study. Why is the foundation helping 23andMe to encourage people with the condition to participate in this research?  </h6>
We share 23andMe’s commitment to advancing research and believe genetics could be vital to finding new insights into scleroderma. Supporting <a href="https://www.23andme.com/systemic-sclerosis-study/?utm_source=srf&amp;utm_medium=referral&amp;utm_campaign=systemic_sclerosis">this research study</a> and encouraging participation could help accelerate the pace of discovery and make a meaningful impact on finding new treatments and a cure. 23andMe is also unique in that it offers an easy way to participate in research. You don’t have to go to a specific center in a specific city. You can do it from your home and answer questions online, and patients really want to do that.

23andMe Blog

23andMe Blog Team

A Conversation with the Scleroderma Research Foundation’s Gloria Blecha

Earlier this summer, a consortium that included more than 3,000 researchers and scientists from around the world jointly published a summary analysis on genetic clues linked to both the susceptibility to COVID-19 and to the most severe cases of people who contracted the virus.&nbsp;&nbsp;&nbsp;
Published in the journal Nature,<a href="https://www.nature.com/articles/s41586-021-03767-x"> the paper notes</a> 13 genetic associations found in genes or gene regions involved in such things as immune response, blood type, and lung disease.
The findings help shed light on the biological pathways in not just how people become sick with the virus but why some people become severely ill from it. The hope is that these <a href="https://www.23andme.com/dna-health-ancestry" target="_blank" rel="noopener">genetic insights</a> will help researchers hunting for therapeutics for treating the virus.
“The better we get at treating COVID-19, the better equipped the medical community could be to manage the disease,” said<a href="https://www.broadinstitute.org/node/7003"> Ben Neale</a>, co-director of the<a href="https://www.broadinstitute.org/node/8507"> Program in Medical and Population Genetics</a> at the Broad and co-senior author of the study. “If we had a mechanism of treating infection and getting someone out of the hospital, that would radically alter our public health response.”
But almost as striking as the genetic findings are the level of collaboration among scientists that formed into this loose consortium known as the<a href="https://www.covid19hg.org/"> COVID-19 Host Genetics Initiative</a>. The initiative began in March of 2020 by scientists at the<a href="https://www.fimm.fi/en/"> Institute for Molecular Medicine Finland, University of Helsinki</a>, and the Broad Institute of MIT and Harvard, and quickly grew from there.&nbsp;
Among the researchers are those from both the private and public sector, from academic institutions and public companies — including scientists from 23andMe — who joined forces to pool what they’ve learned.
“This has exceeded anything I’ve seen in my lifetime,” said Janie Shelton, a 23andMe senior scientist, and epidemiologist. “The rate we’ve been able to collaborate with international teams to uncover the genetic vulnerability to COVID-19 has been incredible.”
Over the last year, several participants in the initiative have already published their findings that ultimately became part of this broader paper. For instance, 23andMe published last June on our findings around genetic associations between the genes that <a href="https://blog.23andme.com/23andme-research/blood-type-and-covid-19/">influence blood type</a> and a person’s susceptibility to COVID-19 and the severity of their symptoms. This year, we published on genetic associations with COVID-19 and<a href="https://blog.23andme.com/23andme-research/scientists-find-genetic-link-to-loss-of-smell-among-covid-19-patients/"> loss of smell and taste</a>, as well as created a tool to help people better understand<a href="https://blog.23andme.com/health-traits/covid-19-severity-calculator/"> the non-genetic factors</a> that contribute to a higher risk for hospitalization due to the virus.
Since launching our<a href="https://you.23andme.com/covid19-study/"> COVID-19 Research Study</a> soon after the pandemic began, we have been sharing our findings with the broader scientific and medical community to help address this health crisis.
As Janie said in an interview earlier this year:
“It’s important for us to unveil our findings as publicly as possible.”
The researchers now plan to focus their attention on so-called “long-haulers,” people who have had the virus who continue to have symptoms for months.
You can read more about the paper<a href="https://www.nature.com/articles/s41586-021-03767-x"> here</a>.
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A logo for 23andMe's COVID-19 Research Study

Scientists Cooperate to Map the Human Genetics of COVID-19

Recently we chatted with Bill Vick, founder of <a href="https://pfwarriors.com/">PF Warriors</a>, a non-profit group for people living with pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF).
<h2>A Rare Disease</h2>
Being diagnosed with IPF, as with many other rare diseases, can feel both overwhelming and bewildering. For many, the first time they&#8217;ve heard about the condition is when they get a diagnosis. IPF results in irreparable scarring of the lungs, which progressively worsens lung function. It&#8217;s terminal, and there is no cure. But there is some promising research underway, and last year, <a href="https://www.23andme.com/dna-health-ancestry" target="_blank" rel="noopener">23andMe</a> launched a genetic study of <a href="https://www.23andme.com/idiopathic-pulmonary-fibrosis/">idiopathic pulmonary fibrosis</a>. We connected with Bill and PF Warriors through that work.
Bill&#8217;s journey might explain the use of the word &#8220;warrior&#8221; in naming the group. Before a career as a serial entrepreneur — heading up large sales divisions, launching computer software companies, and creating his own executive recruiting firm — Bill was a Force Recon Marine. After he retired from business, he became a competitive masters division athlete and brought that same kind of intensity first tapped into as a Marine and then cultivated working in the corporate world. To prepare for competition he included daily runs, swims, weight lifting, or workouts in the gym. It was while training for a competition that he noticed his swim times dropping. He also noticed that he sometimes had difficulty catching his breath.
It took a while to get a diagnosis, and when he did, it was jarring. He had never heard of Idiopathic Pulmonary Fibrosis before, and he didn&#8217;t know how he got it. (Idiopathic means no known cause.) And he was told there was no treatment. So after coming home from the doctor that day, he and his wife Patti decided that he should get his affairs in order, and then the two of them could knock off their &#8220;bucket list&#8221; of things to do while Bill still could. So they celebrated their 50th wedding anniversary. Bill was 72 at the time. He thought he only had two or three years to live.
But that was ten years ago.
<img loading="lazy" decoding="async" class="aligncenter size-full wp-image-28929" src="http://35.88.189.111/wp-content/uploads/2021/06/Bill_Vick_Running.jpg" alt="" width="800" height="600" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/06/Bill_Vick_Running.jpg 800w, https://blogcms.23andme.com/wp-content/uploads/2021/06/Bill_Vick_Running-300x225.jpg 300w, https://blogcms.23andme.com/wp-content/uploads/2021/06/Bill_Vick_Running-768x576.jpg 768w" sizes="auto, (max-width: 800px) 100vw, 800px" />
<h2>What are some of the common themes you&#8217;ve heard from people about first getting diagnosed?</h2>
I, like many, was diagnosed by chance as I had a cough, weight loss, and shortness of breath that my family doctor could not explain. And you know, if I hadn&#8217;t been training so hard and been so in tune with minor changes in my body, I might not have noticed.
I was 72, but I was an active triathlete, and I&#8217;d been a competitive jock all my life. I was training for a short course race here in Texas and started noticing my swim times dropping. So I went to my doctor, and he thought it might be athletic asthma or bronchitis or COPD, and gave me an inhaler, and then a nebulizer. But that didn&#8217;t help much. I think that went on for about a year before I went to a pulmonologist. They did a high-resolution CT scan and a biopsy.
When the results were in, they called and told me to come in and bring my wife, Patti. So we were ushered into a small waiting room, and the doctor comes in and says:
“You&#8217;ve got a rare disease, IPF. It&#8217;s a lung disease with no cure and nothing to stop it. You should go home and get your affairs in order.&#8221;
<h2>Why are so few people, including doctors, aware of IPF? </h2>
Well, it&#8217;s a rare disease. I think my doctor had seen maybe one or two other people with it in his whole career. So when I got my diagnosis, there just weren&#8217;t many resources out there to find out more. And that&#8217;s one of the reasons we started PF Warriors. As I talk to other patients and groups, the same kinds of questions come up. That&#8217;s why it helps to hear from others who are going through the same thing. We now have 2,400 members worldwide and are located in 19 countries.
It took me a couple of years, but I got to this point that I wasn&#8217;t saying that I&#8217;m dying from this disease, but that I&#8217;m living with it.
<h2>Typically, the survival rate after diagnosis is two to three years. You got your diagnosis a decade ago. How have you been able to do so well for so long?</h2>
My advantage was that I was a competitive athlete attuned to my body. So not only was I in great shape but I got diagnosed perhaps earlier because I very quickly noticed the changes in my body.
But we don&#8217;t really know a lot about this disease. There&#8217;s still a lot of ignorance out there, and that&#8217;s why we need more research. I&#8217;ve also benefited by being one of the first people prescribed Esbriet® (pirfenidone). I started taking that when I was 75, and it can help slow the scarring of your lungs or progression of pulmonary fibrosis.
A few years ago I talked to a woman who was a fellow IPF patient named Peggy and I asked her about how long I had to live. She said something about hearing the diagnosis of dying in two or three years and she smiled and said:
&#8220;When you can find the expiration date that God tattooed on your bottom, believe it, but until you do, take each day as it comes and live it fully.&#8221;
<div id="attachment_28931" style="width: 890px" class="wp-caption aligncenter"><img loading="lazy" decoding="async" aria-describedby="caption-attachment-28931" class="size-larger wp-image-28931" src="http://35.88.189.111/wp-content/uploads/2021/06/onemoretime-880x668.jpg" alt="" width="880" height="668" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/06/onemoretime-880x668.jpg 880w, https://blogcms.23andme.com/wp-content/uploads/2021/06/onemoretime-300x228.jpg 300w, https://blogcms.23andme.com/wp-content/uploads/2021/06/onemoretime-768x583.jpg 768w, https://blogcms.23andme.com/wp-content/uploads/2021/06/onemoretime.jpg 949w" sizes="auto, (max-width: 880px) 100vw, 880px" />Bill Vic</div>
<h2>What do you think is the biggest value of having an organization like PF Warriors? </h2>
It&#8217;s meeting people like Peggy in Florida with something to say, but it&#8217;s also crowdsourcing information with others, having a place where you can go for information or questions or support. You know, if you have a doctor who you talk to, that&#8217;s a certain channel for information but talking to someone like you who has it, it&#8217;s a different kind of conversation.
<h2>Recently you invited 23andMe&#8217;s John Matthews to speak to your group. He is the Senior Clinical Development Leader for Therapeutics at 23andMe. He is also a physician who trained in pulmonary medicine. Why did you ask him to speak, and what did he share with you? </h2>
John discussed 23andMe&#8217;s work in drug discovery and 23andMe&#8217;s ongoing effort to recruit 1,000 people for a <a href="https://www.23andme.com/idiopathic-pulmonary-fibrosis/">genetic study on IPF</a>. As a result, we&#8217;ve had other researchers and leading scientists in the field to talk. It&#8217;s a way for us to stay informed and keep ahead of the curve. John walked through the role genetics plays in disease and how 23andMe uses genetic information and other information to find potential drug targets. He also answered a lot of questions from our members who participated in the discussion.
<h2>What are your thoughts about the potential for finding new treatments?</h2>
I think studies like this, using genetics, are critical. But it isn&#8217;t easy to get enough people (with IPF) to participate. This is a similar problem with clinical trials, simply finding people willing to participate, but you need people if you want to see significant breakthroughs. I&#8217;m hoping we can help 23andMe with that. I&#8217;m optimistic that we will find a cure and treatment, maybe I won&#8217;t be around to see it, but I want to do whatever I can to help.
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Living with Idiopathic Pulmonary Fibrosis

Researchers at 23andMe described what is believed to be the largest genomic study of rare diseases ever done in a groundbreaking <a href="https://www.medrxiv.org/content/10.1101/2021.06.09.21258643v1">new paper</a>. The study, published in the pre-print server MedRxiv, offers up a potential alternative method for gaining insight into these challenging-to-study conditions.
Using data from more than 1.6 million research participants, including 19,000 who reported a rare disease diagnosis, 23andMe scientists were able to study 33 different rare diseases that included people of European, African, Latino, East Asian, South Asian, Middle Eastern, and other ancestries. 
<h6>Some Firsts</h6>
The researchers were then able to run genome-wide association studies (GWAS) for each of these different rare diseases. They replicated 29 previously identified associations across different rare diseases. For three of these rare conditions — <a href="https://rarediseases.org/rare-diseases/duane-syndrome/">Duane retraction syndrome</a>, <a href="https://rarediseases.org/rare-diseases/acoustic-neuroma/">vestibular schwannoma</a>, and <a href="https://rarediseases.org/gard-rare-disease/primary-spontaneous-pneumothorax/">spontaneous pneumothorax</a> — the 23andMe study is the first GWAS ever done. The study identified new genetic associations for each. 
The conventional method for studying rare diseases entails sequencing patients with the condition or their family members. Then to use that data to focus on potentially causal genes, but the challenge is to first simply finding enough patients for a study and then paying for the much higher cost of sequencing them. 
<h6>A New Way </h6>
23andMe’s model is different in that the scale of the data allows researchers to quickly find sufficient numbers of cases, and those individuals, who have consented to participate in research, are already genotyped.
“This is exciting because it offers a viable alternative for studying rare diseases,” said Suyash Shringarpure, Ph.D., a 23andMe senior scientist, and statistical geneticist, who worked on the study. “This approach will enable us to discover new genetic associations across multiple populations much faster than could be done otherwise. And it’s complementary to a sequencing-based approach.”
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 <figure class="wp-block-image size-large is-style-default"><img loading="lazy" decoding="async" width="745" height="1024" src="https://blogcms.23andme.com/wp-content/uploads/2021/06/©PITER2017Suyash-Shringarpure2649-745x1024.jpg" alt="" class="wp-image-28941" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/06/©PITER2017Suyash-Shringarpure2649-745x1024.jpg 745w, https://blogcms.23andme.com/wp-content/uploads/2021/06/©PITER2017Suyash-Shringarpure2649-218x300.jpg 218w, https://blogcms.23andme.com/wp-content/uploads/2021/06/©PITER2017Suyash-Shringarpure2649-768x1056.jpg 768w, https://blogcms.23andme.com/wp-content/uploads/2021/06/©PITER2017Suyash-Shringarpure2649-640x880.jpg 640w, https://blogcms.23andme.com/wp-content/uploads/2021/06/©PITER2017Suyash-Shringarpure2649-858x1180.jpg 858w, https://blogcms.23andme.com/wp-content/uploads/2021/06/©PITER2017Suyash-Shringarpure2649-scaled.jpg 1862w" sizes="auto, (max-width: 745px) 100vw, 745px" /></figure>
 
It can often feel like being lost in the wilderness for patients living with a rare disease and their families. With so little information about the conditions, simply receiving a diagnosis can often take years. And once diagnosed, treatment options are often limited or even non-existent.
For the scientists trying to help, it can often feel like being asked to lead those patients out of the wilderness without a map.
<h6>Studying IPF and Systemic Sclerosis </h6>
The challenge of studying <a href="https://rarediseases.info.nih.gov/">rare diseases</a> is that they are rare. Simply finding enough people with a specific rare disease and then gathering enough data from those individuals to make meaningful insights is extremely difficult. In addition, there is the challenge of finding the money to pay for these studies. Rare diseases are defined as diseases that affect fewer than 200,000 people in the U.S. But there are more than 7,000 rare diseases that have been identified. Collectively they impact an estimated <a href="https://rarediseases.info.nih.gov/about-ordr/pages/31/frequently-asked-questions">25-30 million people </a>in the United States alone. 
23andMe is currently recruiting to study two rare diseases <a href="https://www.23andme.com/systemic-sclerosis-study/">systemic sclerosis</a>, a form of scleroderma, and <a href="https://www.23andme.com/idiopathic-pulmonary-fibrosis/">idiopathic pulmonary fibrosis (IPF)</a>, a chronic progressive lung disease. There are no cures for either condition, but the hope is that by gathering enough participants our scientists will be able to gather insights that could lead to new and effective treatments. 
<h6>Surprising Insights</h6>
Beyond working specifically on these two conditions, 23andMe’s unique research model allows scientists to more easily and quickly assemble data to study. This most recent paper illustrated how even looking broadly across all research participants, scientists were able to find enough individuals with certain rare conditions to garner insights. In some cases, these insights surprised researchers. 
For example, many rare diseases are Mendelian diseases, meaning that they are usually inherited and are typically caused by a mutation in a single gene. From this study, the researchers found that <a href="https://www.23andme.com/dna-health-ancestry" target="_blank" rel="noopener">common genetic variants</a> may also play a role in some of these conditions. Given the variety in the genetic architecture of rare diseases, it surprised the scientists working on this study that they found associations in rare causal genes by conducting genome-wide associations studies on 23andMe’s data. Typically genome-wide association studies are used to study common diseases — those that are affected not just by many different genes often with small impacts. These conditions are also influenced by environmental factors as well as gene-by-gene or gene-by-environment interactions. So it surprised researchers that they were able to look at a dataset of unrelated individuals — albeit a very large one — and find genetic associations. But they were able to do that for conditions such as Huntington’s disease and phenylketonuria, for example.
“The ability of a genome-wide association study to find associations at rare causal genes for monogenic diseases in an outbred population is to some extent unexpected,” Suyash said.

New Insights into the Use of Genetics to Study Rare Disease

Researchers at Kaiser Permanente identified dozens of new genetic associations for increased risk of age-related cataracts, one of the leading causes of blindness worldwide.
The study, published in the journal <a href="https://www.nature.com/articles/s41467-021-23873-8?utm_source=feedburner&#038;utm_medium=feed&#038;utm_campaign=Feed%3A+ncomms%2Frss%2Fcurrent+%28Nature+Communications+-+current%29">Nature Communications,</a> also identified genetic associations that are specific to the risk of cataracts for women. The condition is more common among women and this specific association may help explain why.
<h6>Large Study</h6>
The large size of the study, which included data from more than 3.5 million individuals, helped researchers identify many more genetic associations than previously known. This study identified more than 54 genetic associations in dozens of genes, including some that are involved in the development of the lens within our eyes.
While genetics explains some of the risks for developing cataracts, environment, and lifestyle can also play a role. Smoking, eye injuries, and certain medications, for instance, all can increase the risk of developing cataracts. Cataracts tend to develop as we age. Some estimates are that<a href="https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/cataracts"> more than half of those over 80</a> have cataracts or have had surgery to remove them.  Cataracts are characterized by a clouding of the lens that can cause blurry vision, a loss of the vividness of color, or the ability to see at night. In more serious cases, cataracts can lead to blindness.
<h6>Deeper Understanding</h6>
By understanding the associated genes, it can also help identify those at higher risk for the condition. This could allow for earlier treatment, said the author of the paper Hélène Choquet, Ph.D., a research scientist at the Kaiser Permanente Division of Research. 
“This is the first step, and we can use this information along with other factors to build predictive models to identify people more likely to develop cataracts,” Choquet said. “If we can screen people before they develop a disease that would help them and their doctors to quickly identify when a cataract is forming.” 
Thought to be the largest genetic study of cataracts ever the research included data from more than half a million people drawn from Kaiser Permanente, the UK Biobank, which included about 67,000 with cataracts. The researchers then replicated their findings by using data from more than 3 million, including more than 340,000 with cataracts, from 23andMe who consented to participate in research.
<h6>Better Representation</h6>
The large study also included data from people of non-European ancestry, which are underrepresented in genetic research. In this case, 37 of the new genetic associations cut across different ancestries. In addition two of the associations were found in just women.
The data came from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. This cohort includes a group of more than 100,000 Kaiser Permanente Northern California members who volunteered their genetic and medical information for research. GERA is part of the Kaiser Permanente Research Program on Genes, Environment, and Health, which is itself part of the Kaiser Permanente Research Bank. Researchers also used data from the UK Biobank. The UK Biobank contains <a href="https://www.23andme.com/dna-health-ancestry" target="_blank" rel="noopener">genetic and health information</a> from about a half-million residents of the United Kingdom. The replication study used data from more than 3 million 23andMe customers who consented to participate in research.
The researchers also looked at the genes identified through this study and analyzed their function in a database with information on how these same genes express themselves in mice. That analysis confirmed that many of the genetic associations identified in the study were also seen in data on gene expression in mouse eye lens tissue.
“If the gene is expressed in the tissue that means it could have a direct relationship to the development of a cataract, which is caused by crystallization of the lens,” Choquet said.
Funding for the study came from several sources including the National Institutes of Health and in particular the National Eye Institute. 
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New Research Offers Insights into Cataracts

By Jey McCreight, PhD, Science Communication Sr. Program Manager
Pride month is a chance to celebrate the LGBTQ+ community, which is important here at 23andMe where part of our job is understanding and celebrating human diversity. But we should not forget that Pride started as a protest for LGBTQ+ rights, and despite the progress we have made, there is still work ahead.
The last year during this pandemic has been a stressful time for all of us, but even more so for transgender people, especially during the last six months as cultural conversations have shifted to put trans rights at risk. In fact, 2021 has already become the worst year in recent history for <a href="https://www.hrc.org/press-releases/2021-officially-becomes-worst-year-in-recent-history-for-lgbtq-state-legislative-attacks-as-unprecedented-number-of-states-enact-record-shattering-number-of-anti-lgbtq-measures-into-law">anti-LGBTQ legislation in the US</a>. There have been more than 250 anti-LGBTQ bills introduced in state legislatures, and seventeen of those have already been enacted into law. These bills disproportionately target transgender people, especially youth. This year is also <a href="https://www.hrc.org/resources/fatal-violence-against-the-transgender-and-gender-non-conforming-community-in-2021">on track to become the most violent, fatal year</a> for the trans and gender non-conforming community.
Why are we bringing this up? Because these attacks and this legislation have real implications for the health and wellbeing for trans people. For us here at 23andMe, where science is at our core, it’s particularly painful to see some of these legislative efforts pushed under the rallying cry of “trust the science.” As a health company, we feel compelled to speak up about what the science actually says.
People who fear or distrust trans people often use “biology” as a justification for attacking this community. But the reality is that the biology of sex and gender is more complicated than a simple binary. The science shows us that sex itself is <a href="https://blog.23andme.com/23andme-research/how-was-your-sex-determined-it-might-be-a-lot-more-complicated-than-you-think/">not binary, but rather bimoda</a>l, with a range of diversity between the categories of male or female. Scientific research also <a href="https://blog.23andme.com/23andme-and-you/genetics-101/celebrating-pride-month-a-spotlight-on-sex-and-gender/">supports the existence of trans and non-binary gender identities</a> as a natural part of human diversity that have existed throughout history. 
But it is not enough to simply say “trans people exist.” Science also shows that trans people who are accepted and affirmed have better health outcomes and quality of life. 

 <figure class="wp-block-image size-large is-style-default"><img loading="lazy" decoding="async" width="1024" height="614" src="https://blogcms.23andme.com/wp-content/uploads/2021/05/lgbtq-1024x614.png" alt="" class="wp-image-28914" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/lgbtq-1024x614.png 1024w, https://blogcms.23andme.com/wp-content/uploads/2021/05/lgbtq-300x180.png 300w, https://blogcms.23andme.com/wp-content/uploads/2021/05/lgbtq-768x461.png 768w, https://blogcms.23andme.com/wp-content/uploads/2021/05/lgbtq-880x528.png 880w, https://blogcms.23andme.com/wp-content/uploads/2021/05/lgbtq-1180x708.png 1180w, https://blogcms.23andme.com/wp-content/uploads/2021/05/lgbtq.png 1200w" sizes="auto, (max-width: 1024px) 100vw, 1024px" /></figure>
 
<h6>Supporting Social Transition</h6>
<div style="float: right; text-align: justified; width: 300px; background-color: #eee; padding: 15px; margin-left: 10px;">
Terms
Non-binary is an umbrella term to describe gender identities that cannot be described as entirely “male” or “female” (e.g. agender, androgyne, genderfluid, genderqueer, and more.)
Some non-binary people consider themselves to be transgender, while others do not.
</div>
The most well-established treatment protocol for gender dysphoria is social transition, which involves adopting a new name, using different pronouns, changing hair and clothing, and using public spaces associated with one’s gender identity. For trans youth in particular, studies have shown that <a href="https://pediatrics.aappublications.org/content/134/4/696?ijkey=61ee57685e1e08e366a9f122ecec4242d0864f87&#038;keytype2=tf_ipsecsha">having supportive family members</a> is associated with better mental and physical health. Trans adolescents who receive gender affirmation <a href="https://pubmed.ncbi.nlm.nih.gov/21587245/">have better academic success, relationship building, and future-orientated planning.</a> Simply <a href="https://news.utexas.edu/2018/03/30/name-use-matters-for-transgender-youths-mental-health/">using a trans youth’s chosen name</a> and <a href="https://www.thetrevorproject.org/2020/07/29/research-brief-pronouns-usage-among-lgbtq-youth/">respecting their pronouns</a> significantly reduces their risk of depression and suicide.
Social transition also includes allowing trans individuals to play on sports teams that match their gender identity. Despite the wave of legislation attempting to ban trans youth from participating in sports, <a href="https://www.scientificamerican.com/article/trans-girls-belong-on-girls-sports-teams/">there is no scientific evidence</a> that trans girls have inherent advantages over cis girls in sports that justify blanket bans.
<h6>Bathroom Access</h6>
<a href="https://www.ama-assn.org/delivering-care/population-care/advocating-lgbtq-community">Medical experts</a> also support allowing trans people to use bathrooms and other single-sex spaces that are in accordance with one’s gender identity. Laws that seek to force trans individuals to use a restroom that does not correspond with their gender identity increases the risk for trans people to experience harassment and violent assault. <a href="https://static1.squarespace.com/static/54f76238e4b03766696d8f4c/t/5782a8d9197aeaa57b589608/1468180715744/USTS-Preliminary-Findings-July-2016-2.pdf">Trans people often avoid public restrooms</a> because of fear of confrontation or worse, which can lead to higher rates of dehydration, kidney issues, and urinary tract infections.
<h6>Gender-affirming health care</h6>
<a href="https://www.ama-assn.org/delivering-care/population-care/advocating-lgbtq-community">The American Medical Association</a> supports gender-affirming health care, such as hormones and surgery, as receiving such care has been shown to dramatically reduce rates of suicide attempts, depression and anxiety, and substance abuse. Studies by the <a href="https://pediatrics.aappublications.org/content/145/2/e20191725">American Academy of Pediatrics</a>, Cornell University, and other institutions have found that pubertal suppression treatment for trans youth was associated with lower odds of suicidal thoughts. Despite <a href="https://jamanetwork.com/journals/jama/fullarticle/2780517">most mainstream medical associations opposing legislation</a> that limits gender affirming medical care for trans youth, this health care <a href="https://www.nbcnews.com/feature/nbc-out/arkansas-passes-bill-ban-gender-affirming-care-trans-youth-n1262412">has already been banned in the state of Arkansas</a>.
<div style="float: right; text-align: justified; width: 300px; background-color: #eee; padding: 15px; margin-left: 10px;">
Medical Opinion
The following medical associations oppose legislation that limits gender-affirming medical care for trans youth:
• American Medical Association
• American College of Physicians
• American Academy of Family Physicians
• American College of Obstetricians and Gynecologists
• American Osteopathic Association
• American Psychiatric Association
• American Academy of Pediatrics
• American Academy of Child and Adolescent Psychiatry
• The Endocrine Society
• The Pediatric Endocrine Society
• World Professional Association for Transgender Health
• US Professional Association for Trangender Health.
&nbsp;
</div>
<h6>Mental health</h6>
To be clear, there is no evidence that increased risk for mental illness among trans people is due to being transgender. The American Psychological Association and American Psychiatric Association have both firmly stated that <a href="https://pediatrics.aappublications.org/content/142/4/e20182162">this increased risk stems from stigma, social rejection, discrimination, and limited availability of gender-affirming health care services.</a>
<h6>What 23andMe is Doing in Product</h6>
To put it succinctly, there is no debate among the medical and scientific communities when it comes to accepting and affirming the gender identities of trans people.
This is why we have spent the last year working to improve our product experience for trans and non-binary customers. This has included research on best practices recommended by LGBTQ organizations, conducting focus groups with trans customers, and consulting trans employees. When these improvements go live later this year, customers will be able to input both their sex assigned at birth and their gender during kit registration and will be able to select the relationship labels (e.g. father, uncle, brother) that best reflect their gender identity, including gender-neutral options. The option to use gender-neutral pronouns is also available to cisgender customers who may want their gender anonymous for privacy reasons. 
This is only the first step in an overall commitment to improving our offerings for trans customers. As more research becomes available, for example on how hormone replacement therapy may affect risk estimates, we hope to keep improving our reports so they are more relevant for trans customers.
<h6>A Personal Conclusion</h6>
It’s easy to read a blog post on a company site and think it’s some detached statement. But I myself am a non-binary trans person. I’m hesitant to say this because I worry that some readers will no longer trust the scientific content of this post, despite my Ph.D. or my role leading 23andMe’s Science Communication program.
That fear of turning most of society against me is why I, like so many other trans people, stayed in the closet for so long. I was terrified that coming out would ruin my career, lose my family and friends, and put me at risk of violence. That fear directly came from the media I watched growing up, which cast trans people as monsters to be feared, pitied, or ridiculed. 
But a cultural shift is clearly happening. I finally found resources and language to describe how I’ve always felt, and to realize there were other people out there like me. I met trans people in real life and saw more role models in the media that showed me that, frankly, there is nothing wrong with being trans. 
I feel lucky to work at a place where I felt comfortable enough to publicly transition without losing my job or the respect of my colleagues. Being able to have that job security, which most trans people do not, enabled me to finally be myself completely openly, including to my closest family and friends. 
Do coworkers and family still occasionally mess up my pronouns? Yes. But overall I’ve been privileged by how supportive everyone has been. I can tell they’re making an effort to do better and to learn why affirming my gender matters so much to me because they care about my health and happiness. That willingness to learn sets them apart from transphobes who refuse to listen to scientists, doctors, and most importantly, trans people themselves.
But not every trans person is as privileged as I am. Many think trans people only care about pronouns, but from legislative attacks to literal violent attacks, it is a dangerous time to be trans. Trans people of color in particular are disproportionately affected by violence, discrimination, and lack of health care. Trans youth are already having life-saving gender-affirming health care made illegal, despite medical consensus supporting that care. I wish I would have had the support and science to not go through the wrong puberty, and it breaks my heart to watch kids have that taken away.
The least I can do from my position of privilege is to speak up. Regardless of what science says, everyone should still treat trans people with respect because it’s just the right thing to do. But if you want to claim you “trust the science” in order to attack trans people, then sorry &#8211; the science says that trans rights are human rights.

Trust the Science by Supporting Trans Health Care

Researchers at 23andMe have identified a new <a href="https://www.23andme.com/dna-health-ancestry" target="_blank" rel="noopener">genetic variant</a> associated with COVID-19 induced loss of smell and taste.
The findings, published in a preprint released on <a href="https://www.medrxiv.org/content/10.1101/2021.05.28.21257993v1">medRxiv</a>, note that the genetic variant is near two olfactory genes.  Loss of smell and, or taste — also called anosmia — is a hallmark symptom of COVID-19. It is often the earliest indication of infection, and in some cases, the only symptom. An individual with one copy of the variant is about 11.5 percent more likely to lose their sense of smell or taste if infected compared to someone with zero copies.
<h6>23andMe COVID-19 Study</h6>
The research adds another piece to the COVID-19 puzzle, and it builds on the work already done by 23andMe over the last year that includes new findings around <a href="https://blog.23andme.com/23andme-research/23andme-covid-study-published/">the role blood type plays </a>in severity and susceptibility to the virus. This piece of the puzzle is intriguing because the novel coronavirus SARS-CoV-2 first enters the body and accumulates in olfactory support cells. The findings may offer researchers important insights into the <a href="https://www.23andme.com/dna-health-ancestry" target="_blank" rel="noopener">biological pathway for infection</a>.
For these findings, the researchers again used data from more than one million people who consented to participate in 23andMe’s <a href="https://you.23andme.com/covid19-study/">COVID-19 Study</a>.  By examining the differences in the genome between COVID-19 cases who did and did not experience loss of taste or smell, our scientists identified an association on chromosome 4 near the olfactory genes UGT2A1 and UGT2A2 (Figure 1 and Figure 2a). 
<div id="attachment_28919" style="width: 890px" class="wp-caption aligncenter"><img loading="lazy" decoding="async" aria-describedby="caption-attachment-28919" class="size-larger wp-image-28919" src="http://35.88.189.111/wp-content/uploads/2021/05/ugt2a1-2-880x451.png" alt="A Manhattan plot showing a strong association in the genes UGT2a1/2" width="880" height="451" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/ugt2a1-2-880x451.png 880w, https://blogcms.23andme.com/wp-content/uploads/2021/05/ugt2a1-2-300x154.png 300w, https://blogcms.23andme.com/wp-content/uploads/2021/05/ugt2a1-2-768x394.png 768w, https://blogcms.23andme.com/wp-content/uploads/2021/05/ugt2a1-2-1024x525.png 1024w, https://blogcms.23andme.com/wp-content/uploads/2021/05/ugt2a1-2-1180x605.png 1180w, https://blogcms.23andme.com/wp-content/uploads/2021/05/ugt2a1-2.png 1494w" sizes="auto, (max-width: 880px) 100vw, 880px" />Figure 1. Manhattan plot of loss of smell vs. no loss of smell among those with a positive SARS-CoV-2 test.</div>
<h6>Relevant for All Ethnicities</h6>
The scientists ran separate genome-wide association studies for individuals of European, Latino, African American, East Asian, and South Asian ancestries, and then combined the data via a meta-analysis. The researchers evaluated the effect of the top-associated single nucleotide polymorphism (SNP) in the different ancestral populations (Figure 2).
<div id="attachment_28918" style="width: 522px" class="wp-caption aligncenter"><img loading="lazy" decoding="async" aria-describedby="caption-attachment-28918" class="size-full wp-image-28918" src="http://35.88.189.111/wp-content/uploads/2021/05/COVID-smell-snp-plot.png" alt="" width="512" height="398" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/COVID-smell-snp-plot.png 512w, https://blogcms.23andme.com/wp-content/uploads/2021/05/COVID-smell-snp-plot-300x233.png 300w" sizes="auto, (max-width: 512px) 100vw, 512px" />Figure 2a. Regional plot of the association detected in the vicinity of UGT2A1/2. </div>
<div id="attachment_28917" style="width: 522px" class="wp-caption aligncenter"><img loading="lazy" decoding="async" aria-describedby="caption-attachment-28917" class="size-full wp-image-28917" src="http://35.88.189.111/wp-content/uploads/2021/05/Covid-smell-p-values.png" alt="" width="512" height="315" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/Covid-smell-p-values.png 512w, https://blogcms.23andme.com/wp-content/uploads/2021/05/Covid-smell-p-values-300x185.png 300w" sizes="auto, (max-width: 512px) 100vw, 512px" /> Figure 2b. Population effect sizes and 95% confidence intervals.</div>
Those results show no evidence of a difference in the SNP effect between populations, although there is limited power to detect associations in the non-European populations. Nonetheless, the frequency of the risk allele does differ somewhat by population. It is most commonly observed in individuals of European ancestry (37 percent) and least commonly observed in individuals of East Asian ancestry (19 percent) (Table 1).
<table>
<tbody>
<tr>
<td>Population</td>
<td>Variant frequency</td>
</tr>
<tr>
<td>Europe</td>
<td>37%</td>
</tr>
<tr>
<td>South Asian</td>
<td>32%</td>
</tr>
<tr>
<td>African American</td>
<td>31%</td>
</tr>
<tr>
<td>Latino</td>
<td>30%</td>
</tr>
<tr>
<td>East Asian</td>
<td>19%</td>
</tr>
</tbody>
</table>
Table 1. Allele frequencies by population or rs7688383
<h6>Among the Most Common Symptoms</h6>
Early in the outbreak, the loss of smell and taste was recognized as a means to distinguish between patients with COVID-19 and those with simple colds or flu. That is, if you felt sick and had a loss of smell or taste, you were much more likely to have COVID-19 than another respiratory infection (<a href="https://www.nature.com/articles/s41591-020-0916-2">1</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386529.1/">2</a>).
In the 23andMe COVID-19 study, two-thirds (68 percent) of those who tested positive for the virus reported loss of smell or taste, compared to just 17 percent of those who tested negative (Figure 3). Furthermore, in a model adjusted for other symptoms, age, and sex, the loss of smell or taste carried a seven-fold increased likelihood of testing positive for SARS-CoV-2 among those reporting illness.
<div id="attachment_28916" style="width: 522px" class="wp-caption aligncenter"><img loading="lazy" decoding="async" aria-describedby="caption-attachment-28916" class="size-full wp-image-28916" src="http://35.88.189.111/wp-content/uploads/2021/05/COVID-symptoms.png" alt="" width="512" height="316" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/COVID-symptoms.png 512w, https://blogcms.23andme.com/wp-content/uploads/2021/05/COVID-symptoms-300x185.png 300w" sizes="auto, (max-width: 512px) 100vw, 512px" />Figure 3. Frequency of symptoms reported among respondents with a cold or flu-like illness who did and did not have a positive SARS-CoV-2 result in the 23andMe study, ordered by percentage difference.</div>
<h6>Looking by Age</h6>
When the researchers looked at the symptoms by age, they found that among younger people with COVID-19 the loss of smell and taste was more common. Among those aged 26-35, 73 percent reported loss of smell, whereas only 43 percent reported loss of smell in those 85 or older (Figure 4). When the researchers looked at differences between men and women they found that women were more likely than men to report loss of smell or taste (72 percent  vs. 61 percent). While it is known that age is associated with lower sensitivity to smell, these findings held up when adjusted for self-reported ability to smell in advance of infection with SARS-CoV-2.
<div id="attachment_28915" style="width: 890px" class="wp-caption aligncenter"><img loading="lazy" decoding="async" aria-describedby="caption-attachment-28915" class="size-larger wp-image-28915" src="http://35.88.189.111/wp-content/uploads/2021/05/Loss-of-Smell-by-Age-880x545.png" alt="" width="880" height="545" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/Loss-of-Smell-by-Age-880x545.png 880w, https://blogcms.23andme.com/wp-content/uploads/2021/05/Loss-of-Smell-by-Age-300x186.png 300w, https://blogcms.23andme.com/wp-content/uploads/2021/05/Loss-of-Smell-by-Age-768x476.png 768w, https://blogcms.23andme.com/wp-content/uploads/2021/05/Loss-of-Smell-by-Age-1024x634.png 1024w, https://blogcms.23andme.com/wp-content/uploads/2021/05/Loss-of-Smell-by-Age-1180x731.png 1180w, https://blogcms.23andme.com/wp-content/uploads/2021/05/Loss-of-Smell-by-Age.png 1544w" sizes="auto, (max-width: 880px) 100vw, 880px" />Figure 4. COVID-19 related loss of smell by age group</div>
<h6>More About the Genetic Association</h6>
Little is known about what the genetic variant (rs7688383) does, or how it impacts the likelihood of losing your smell or taste during infection with SARS-CoV-2. But the olfactory genes UGT2A1/2 are part of a family of enzymes called uridine diphosphate glycosyltransferases and are expressed in the olfactory epithelium and metabolize odorant compounds. In the 23andMe database, both of these genes are related to such things as <a href="https://blog.23andme.com/23andme-research/genes-scream-for-ice-cream/">ice-cream</a> taste preference and ability to smell as measured by a self-reported five-point scale ranging from very poor to very good.
Recent evidence suggests that SARS-CoV-2 enters and accumulates in olfactory support cells, which abundantly express the viral entry proteins ACE2 and TMPRSS2 (<a href="https://advances.sciencemag.org/content/6/31/eabc5801">3</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7241737/">4</a>). It has been proposed that olfactory sensation is impaired when these essential functions are disrupted, causing olfactory receptor neuron cilial impairment (<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488171/https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488171/">5</a>). Given their localization and essential function in the metabolization and detoxification of compounds in the olfactory epithelium, the genes identified here, UGT2A1/2, may play a role in the physiology of infected cells and the resulting changes to the cilia that contribute to our ability to smell.
Many thanks to the over 1 million research participants who answered our questionnaire and made this research possible. 
*The 23andMe COVID-19 research team includes: Adam Auton, Adrian Chubb, Alison Fitch, Alison Kung, Amanda Altman, Andy Kill, Anjali Shastri, Antony Symons, Catherine Weldon, Chelsea Ye, Daniella Coker, Janie Shelton, Jason Tan, Jeff Pollard, Jey McCreight, Jess Bielenberg, John Matthews, Johnny Lee, Lindsey Tran, Maya Lowe, Michelle Agee, Monica Royce, Nate Tang, Pooja Gandhi, Raffaello d’Amore, Ruth Tennen, Scott Dvorak, Scott Hadly, Stella Aslibekyan, Sungmin Park, Taylor Morrow, Teresa Filshtein Sonmez, Trung Le, and Yiwen Zheng. 
[/vc_column_text][/vc_column][/vc_row]

Scientists Find Genetic Link to Loss of Smell Among COVID-19 Patients

By Samantha Ancona Esselmann, Ph.D., and Chelsea Robertson, Ph.D.*
Editor’s note: A version of this post originally appeared earlier this year in our premium content for <a href="https://www.23andme.com/membership" target="_blank" rel="noopener">23andMe+</a> members. We are reposting it on 23andMe&#8217;s blog for Pride Month. In this article, the term “sex” is used in a developmental and biological sense. This article does not focus on sexual orientation or gender identity, which were addressed in a <a href="https://blog.23andme.com/23andme-and-you/genetics-101/celebrating-pride-month-a-spotlight-on-sex-and-gender/">previous blog post</a>.  
A shallow understanding of the mechanisms that determine biological sex might lead one to suppose that sexual development is a simple matter of reading the same recipe and always ending up with the same cookie. It’s not.
We are astonishingly complex bags of organic and inorganic chemicals that defy entropy until we die. You can change the recipe and end up with the same cookie, or follow the same recipe and end up with a completely different cookie. (And, if baking were easy, we wouldn’t have just finished the 10th season of the “Great British Baking Show.”) 
Infinitely more complicated than baking a 20-layer Schichttorte are the biological processes that determine your sex. Your sex, like Schichttorte, has a lot of layers. <img loading="lazy" decoding="async" class="alignright size-medium wp-image-28892" src="https://blog-api.23andme.com/wp-content/uploads/2021/05/cookbook-2-251x300.png" alt="" width="251" height="300" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/cookbook-2-251x300.png 251w, https://blogcms.23andme.com/wp-content/uploads/2021/05/cookbook-2-768x920.png 768w, https://blogcms.23andme.com/wp-content/uploads/2021/05/cookbook-2-855x1024.png 855w, https://blogcms.23andme.com/wp-content/uploads/2021/05/cookbook-2-735x880.png 735w, https://blogcms.23andme.com/wp-content/uploads/2021/05/cookbook-2-985x1180.png 985w, https://blogcms.23andme.com/wp-content/uploads/2021/05/cookbook-2.png 1336w" sizes="auto, (max-width: 251px) 100vw, 251px" />
At the bottom, there’s your chromosomal and genetic sex. There are also sex organs, hormones, and secondary sex characteristics — like beards and breasts. Then, of course, there’s your biggest sex organ, your brain, wherein an incomprehensibly large ensemble of neurons shout, whisper, and sing a symphony of sexual identity that is wholly unique to you.
And while all those layers can be consistent with a binary definition of sex, sex is not binary: Any one of the layers can be swapped out for a different color or texture, or taste. Humans can be intersex.
In a recent 23andMe<a href="https://blog.23andme.com/23andme-and-you/genetics-101/celebrating-pride-month-a-spotlight-on-sex-and-gender/"> blog post</a> about sex and gender, Dr. Jey McCreight explained, “at least one in 1,500 births are intersex, meaning that a person’s anatomy and/or their chromosomes can’t be classified as typically male or female. This is a conservative estimate, as many people do not realize they are intersex until later in life. Some never find out.”
Let’s start at the very beginning.
<h6>The sex gene</h6>
During the first few <a href="https://www.ncbi.nlm.nih.gov/books/NBK279001/">weeks</a> of your life, you were an androgynous mass of cells. In form and face neither male nor female nor even recognizably human, you followed an age-old sequence of gestational milestones, starting with important ones like, “Grow heart!”

 <figure class="wp-block-image size-large is-style-default"><img loading="lazy" decoding="async" width="977" height="1024" src="https://blogcms.23andme.com/wp-content/uploads/2021/05/embryos-with-attribution-977x1024.png" alt="" class="wp-image-28890" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/embryos-with-attribution-977x1024.png 977w, https://blogcms.23andme.com/wp-content/uploads/2021/05/embryos-with-attribution-286x300.png 286w, https://blogcms.23andme.com/wp-content/uploads/2021/05/embryos-with-attribution-768x805.png 768w, https://blogcms.23andme.com/wp-content/uploads/2021/05/embryos-with-attribution-840x880.png 840w, https://blogcms.23andme.com/wp-content/uploads/2021/05/embryos-with-attribution-1126x1180.png 1126w, https://blogcms.23andme.com/wp-content/uploads/2021/05/embryos-with-attribution.png 1336w" sizes="auto, (max-width: 977px) 100vw, 977px" /></figure>
 
As you bobbed and rolled, tethered to life by a spongy tube full of filtered blood, the cells of your primordial gonads still existed in a bi-potential state, meaning they possessed the power to develop and multiply into either ovaries or testes.
Which path these cells eventually followed depended on either the absence or the activation of a gene located on the Y chromosome. That gene is called SRY, or the Sex-determining Region on the Y chromosome&#8230; a very un-sexy name for the “sex gene.”

 <figure class="wp-block-image size-large is-style-default"><img loading="lazy" decoding="async" width="512" height="216" src="https://blogcms.23andme.com/wp-content/uploads/2021/05/sex-chromosome.png" alt="" class="wp-image-28891" srcset="https://blogcms.23andme.com/wp-content/uploads/2021/05/sex-chromosome.png 512w, https://blogcms.23andme.com/wp-content/uploads/2021/05/sex-chromosome-300x127.png 300w" sizes="auto, (max-width: 512px) 100vw, 512px" /></figure>
 
In the absence of SRY activation, the default human embryo is female. But, turn on that switch and, like a soupy Rube-Goldberg machine, a fractal cascade of carefully orchestrated chemical events is initiated, knocking that developing embryo onto a “male” path. This path is not simply a matter of making all the male bits. It also requires a manual override of ovarian development — an active silencing of the default human protocol.
Needless to say, there’s a vas deferens between these two paths.
<h6>Chromosomes and sex</h6>
Through services like 23andMe, people may learn that their chromosomal sex doesn’t match the sex they were assigned at birth. We all fall on slightly different points along a spectrum between typical biological female and typical biological male, but most of us go through life without ever knowing the exact complement of chromosomes in our cells.
You need at least one X chromosome to survive past the tumultuous early days of embryonic development. But beyond this most basic requirement, there’s a lot of wiggle room in the pantheon of chromosomal sex.
Generally, people with no Y chromosome appear biologically female, while people with at least one Y chromosome appear male: Most females are XX, and most males are XY. But there are other combinations too, such as XXX, XXY, XYY, XYYY, XXXY, XXXX, X (also known as XO), and mosaic XY/X or XX/X individuals, whose unusual karyotypes arose from a failure of sex chromosomes to end up in the right place during cell division. (A karyotype is the number and appearance of your chromosomes under a microscope.)
But, your sex isn’t only about which sex chromosomes you have.
<h6>More on chromosomes: Why it’s not all about the Y</h6>
Over tens of millions of years, the Y chromosome’s role in humans has <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4120474/">atrophied</a> to one of ferrying a few genes across the generations to enable us to reproduce sexually.
But, it’s possible to have a Y chromosome and be genetically female, hormonally female, and physically female (meaning you have a Y chromosome but lack a functioning SRY gene). It’s also possible to lack a Y chromosome and be genetically, hormonally, and physically male.
These situations typically arise in a father’s sex cells when there’s a mutation in the SRY gene, or when SRY jumps from a Y chromosome onto an X inside a sex cell — rendering the former almost completely vestigial and conferring the power of sex determination on the latter.
When an SRY-deficient Y chromosome is passed on, the sexual development of the XY fetus <a href="https://www.ncbi.nlm.nih.gov/books/NBK279001/">can</a> follow a similar path to that of a fetus without a Y chromosome. The other side of the same coin can mean that there are XX males who inherited an SRY gene on an X chromosome. There’s even <a href="https://academic.oup.com/molehr/article/12/5/341/1005702">a report</a> of a male with two X chromosomes who lacks the SRY gene, and scientists speculate that mutations in other genes related to sexual development can also promote masculinization. 
And, well, biological sex doesn’t exactly get less complicated from here.
Beyond SRY, sex determination and development also depend on a flurry of hormones that help direct and monitor the progress of the human build, from gestation to adulthood.
<h6>Hormones</h6>
Hormone signaling in the womb affected the progress of your sexual development and, in particular, the shape and formation of your external genitalia — the appearance of which had a big impact on the sex you were assigned at birth.
The assignment of a baby’s biological sex is rarely called into question when the infant&#8217;s genitalia appear “normal” or as expected. But by this point, you can probably guess, biological sex is not as simple as what’s visible in your nether regions.
Certain genetic variants affecting hormone production and signaling can have dramatic effects on the formation of genitalia in the womb. So while you can be XY or XX or X (XO), or any other combination, small changes in hormone production and signaling can push you in different directions along the spectrum of biological sex traits, much like how small changes in humidity or temperature can change the rise of your bake.
Got a variant that boosts your testosterone levels? Might not be noticeable if you are a male (XY) embryo, but XX females with a variant like this may have genitalia at birth that do not appear particularly male or female.
Got a variant that changes the way testosterone transmits signals to the cell? If you&#8217;re a female (XX) embryo you might not have any noticeable signs or symptoms at birth. But if you&#8217;re a male (XY)  embryo, your genitalia may appear more ambiguous.
What about when babies are born with the expected external genitalia, but nevertheless have differences in hormone production and signaling? Sometimes hormonal differences go largely unnoticed until the early teenage years when your hormones return to center stage in Act 2 of your sexual development — puberty.
Got a genetic variant that inhibits the production of testosterone? If you are a male (XY) embryo, it&#8217;s possible that your genitalia could appear female at birth. You could be raised as a female for over a decade, then puberty hits and your body doesn&#8217;t do the normal female puberty thing. Instead, you notice increased muscle mass, some facial hair, and a deeper voice.
So you can be XY, insensitive to the effects of testosterone in the womb, born with female genitalia, then go on to develop male secondary sex characteristics later in life.
Are the lines encircling the concepts of biological sex beginning to blur?
Let&#8217;s recap.
You can be chromosomally and genetically male or female, but depending on your particular hormone production and signaling systems, you might end up somewhere else on the spectrum of biological sex.
Hormonally and physically, you can be somewhere in between male and female.
<h6>So why does this matter?</h6>
Imagine, for a moment, how boring life would be if every baguette came out of the oven the same, or if every birthday cake had the same frosting, or the same filling. The more we understand about the textured, richly flavored layers of sexual development, the better equipped we are to mobilize empathy for others and their diverse experiences.
*Both Samantha and Chelsea are 23andMe Product Scientists, and both hold doctorates in neuroscience.
<hr />
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<li aria-level="1"><a href="https://www.ncbi.nlm.nih.gov/books/NBK279001/">Rey R, Josso N, Racine C. Sexual Differentiation. [Updated 2020 May 27]. In: Feingold KR, Anawalt B, Boyce A, et al., editors.</a></li>
<li aria-level="1">McCreight, J. 2020. “<a href="https://blog.23andme.com/23andme-and-you/genetics-101/celebrating-pride-month-a-spotlight-on-sex-and-gender/">Celebrating Pride Month, a Spotlight on Sex and Gender.</a>” 23andMe blog.</li>
<li aria-level="1">Bachtrog D. (2013). &#8220;Y-chromosome evolution: emerging insights into processes of Y-chromosome degeneration.&#8221; Nat Rev Genet. 14(2):113-24. https://pubmed.ncbi.nlm.nih.gov/23329112/</li>
<li aria-level="1">The Y chromosome is disappearing – so what will happen to men? by Darren Griffin, The Conversation. Retrieved October 25, 2020, from <a href="https://phys.org/news/2018-01-chromosome-men.html">https://phys.org/news/2018-01-chromosome-men.html</a></li>
<li aria-level="1">Montañez A. (2017). &#8220;Beyond XX and XY.&#8221; Sci Am. 317(3):50-51. https://pubmed.ncbi.nlm.nih.gov/28813372/</li>
<li aria-level="1">Gomez-Lobo V et al. (2016). &#8220;Disorders of Sexual Development in Adult Women.&#8221; Obstet Gynecol. 128(5):1162-1173. https://pubmed.ncbi.nlm.nih.gov/27741188/</li>
<li aria-level="1">Ha NQ et al. (2014). &#8220;Hurdling over sex? Sport, science,nd equity.&#8221; Arch Sex Behav. 43(6):1035-42. https://pubmed.ncbi.nlm.nih.gov/25085349/</li>
<li aria-level="1">MedlinePlus (2019, Aug 7). “Intersex.” Retrieved October 31, 2020, from https://medlineplus.gov/ency/article/001669.htm</li>
<li aria-level="1">MedlinePlus (2010, Feb 1) “CYP21A2 gene: Health Conditions Related to Genetic Changes.”  Retrieved October 31, 2020, from https://medlineplus.gov/genetics/gene/cyp21a2/#conditions.</li>
<li aria-level="1">MedlinePlus (2018, Sept 1)“Congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.” Retrieved October 31, 2020, from https://medlineplus.gov/genetics/condition/congenital-adrenal-hyperplasia-due-to-11-beta-hydroxylase-deficiency/</li>
<li aria-level="1">Ohnesorg T et al. (2014). &#8220;The genetics of disorders of sex development in humans.&#8221; Sex Dev. 8(5):262-72. https://pubmed.ncbi.nlm.nih.gov/24504012/</li>
</ol>

How was your sex determined? It might be a lot more complicated than you think

A massive new genome-wide association study led by the U.S. Department of Veteran Affairs is shedding new light on the genetic underpinnings of major depression.
More than 16 million Americans are affected by depression each year, and nearly 6 million Americans suffer from bipolar, according to the National Institutes of Health. However, current treatment options do not always work for people living with these conditions, and researchers hope that new insights into the condition&#8217;s genetics could help diagnose and treat it.
<h2>Million Veterans</h2>
For this study, scientists at Yale and the University of California, San Diego, used data from 1.2 million people to identify 178 genetic variants linked to depression.
The study, published in the journal <a href="https://www.nature.com/articles/s41593-021-00860-2">Nature Neuroscience</a>, included data from the Million Veteran’s Project, the UK Biobank, FinnGen, and from 23andMe customers who consented to participate in research. After the initial study, the researchers cross-checked their findings using an entirely separate cohort from 23andMe that included data from 1.3 million customers who consented to participate in research.
“What is most heartening is that we could replicate our findings in independent data sets,” said Daniel Levey, an associate research scientist in the Yale Department of Psychiatry and co-lead author. “Replication is a hallmark of good science, and this paper points to just how reliable and stable results from GWAS studies are becoming.”
<h2>Brain Development</h2>
A number of the genetic variants identified are giving researchers deeper insight into the underlying biology of depression. Researchers point to variants in or near the gene NEGR1, a neural growth regulator active in the hypothalamus, an area of the brain previously linked to depression.
That confirms research done by the late Yale neuroscientist Ronald Duman on the role of neurotrophic factors in depression, Levey said.
“It’s really striking when completely different kinds of research converge on similar biology, and that’s what’s happening here,” he said.
The size and breadth of the study will also help scientists create models to calculate risk — known as polygenic risk scores — to better estimate the risk of developing major depression or other related psychiatric disorders such as post-traumatic stress disorder and anxiety. Beyond estimating the risk, the hope is that new genetic insights will help in identifying better ways to treat depression and related conditions.
“One of the real goals of the research is bringing forward new ways to treat people suffering from depression,” said co-senior author Dr. Murray Stein, staff psychiatrist at the V.A. San Diego Healthcare System and Distinguished Professor of Psychiatry and Public Health at UCSD.

Research — Page 15