<img loading="lazy" decoding="async" class="alignright size-full wp-image-5313" title="wolf" src="https://blog-api.23andme.com/wp-content/uploads/2009/10/wolf1.jpg" alt="wolf" width="350" height="260" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/10/wolf1.jpg 350w, https://blogcms.23andme.com/wp-content/uploads/2009/10/wolf1-300x223.jpg 300w" sizes="auto, (max-width: 350px) 100vw, 350px" /> 
Lupus, which means &#8220;wolf&#8221; in Latin, gets its name from the skin manifestations sometimes seen in the disease. A physician in the 13th century thought they looked like wolf bites.
In autoimmune disorders, the immune system – which normally protects us from harmful, foreign substances – goes into overdrive and starts attacking the body&#8217;s own cells, causing inflammation and organ damage.
<a href="http://www.nlm.nih.gov/medlineplus/ency/article/000435.htm">Systemic lupus erythematosus</a> (SLE) is an autoimmune disease characterized by chronic, widespread  inflammation that can result in arthritis, fever, skin rashes, muscle aches, seizures and fatigue, among other symptoms.  Some symptoms can even be life-threatening. Between one and seven out of every 10,000 people is affected by SLE. The disease affects women nine times more frequently than men, and tends to be more prevalent and severe in people of non-European descent.  The exact causes of SLE are unknown and there is currently no cure.
For several decades now, researchers have probed the genetic underpinnings of this mysterious disease. Two studies published this week in Nature Genetics identify new genetic variants associated with SLE in European and Asian populations.
In the <a href="https://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.468.html">first study</a>, a team led by Vesela Gateva and Robert Graham of Genentech identified ten novel genetic variants associated with SLE in a European group consisting of more than 3,000 people with the disease and 10,000 people without SLE. Half of these variants were previously associated with other autoimmune diseases, but this is the first time they have been associated with SLE. In addition, the researchers confirmed nine variants previously linked to SLE in other studies.
Of the previously reported autoimmune variants, Gateva and colleagues note that the A version of the variant is also a known risk variant for age-related macular degeneration, seems to be protective against SLE, although additional research will be needed to confirm this effect.
One of the SNPs not previously associated with SLE or any other autoimmune disease,   is in the gene that encodes TNIP1.   The TNIP1 protein is known to interact with TNFAIP3, a protein that genetic studies have previously linked to rheumatoid arthritis, psoriasis and type 1 diabetes – all autoimmune disorders – suggesting that the TNIP1-TNFAIP3 association may play a general role in autoimmunity.
In the <a href="https://www.nature.com/ng/journal/vaop/ncurrent/abs/ng.472.html">second study</a>, Jian-Wen Han and Xue-Jun Zhang’s team from Anhui Medical University in China identified 21 genetic variants associated with SLE in more than 4,000 Chinese individuals with the disease and 8,200 individuals without autoimmune disorders. About half of the associations confirmed previous reports in European populations, and half represented novel findings.
Interestingly, one of the new variants they identified is also in the TNIP1 gene. Here, each copy of a T increased odds of SLE by about 1.24 times. Many other SNPs associated with SLE in the Chinese study were located in or near genes involved in immune response.
The TNIP1-TNFAIP3 connection and association of variants known to be linked to other autoimmune diseases add to growing evidence that common genetic factors contribute to autoimmunity. These findings may help pave the way for novel therapeutics for autoimmune disease that exploit this shared genetic basis.

23andMe Blog

23andMe Blog Team

New Variants Associated With Lupus in Europeans and Asians

<img loading="lazy" decoding="async" class="alignright size-full wp-image-5106" title="iStock_000006370742XSmall" src="https://blog-api.23andme.com/wp-content/uploads/2009/10/iStock_000006370742XSmall.jpg" alt="iStock_000006370742XSmall" width="350" height="263" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/10/iStock_000006370742XSmall.jpg 400w, https://blogcms.23andme.com/wp-content/uploads/2009/10/iStock_000006370742XSmall-300x225.jpg 300w" sizes="auto, (max-width: 350px) 100vw, 350px" />
Previously we discussed two papers that identified <a href="https://blog.23andme.com/articles/snpwatch-genetic-variations-influencing-hemoglobin-levels-identified/">genetic variants associated with hemoglobin levels</a> in circulating blood.
But blood consists of much more than hemoglobin. It is responsible for much more than just transporting oxygen. This week Nature Genetics published the results of two of the largest blood studies to date. Together the studies identified dozens of new variants associated with nine blood-related traits.
<h6>Cellular Components</h6>
In addition to red blood cells, which carry hemoglobin, whole blood contains white blood cells. White blood cells are a crucial part of our immune system. Whole blood also contains platelets, which are important for clotting. All of these cellular components are suspended in a protein-rich plasma that makes up most of the volume of blood, and maintains the pressure needed to deliver the blood&#8217;s cargo throughout a person’s body.
Like hemoglobin levels, measurements of other blood traits can be informative about health. An abnormally high white blood cell count and platelet volume have both been linked to an increased risk for heart attack. These measurements can also indicate the presence of infectious disease, immunological disorders or cancers.
<a href="https://dx.doi.org/10.1038/ng.467">Nicole Soranzo and her colleagues in the HaemGen consortium</a> measured hemoglobin concentration (Hb), red blood cell count (RBC), red blood cell volume (MCV), platelet count (PLT), platelet volume (MPV), white blood cell count (WBC), the amount of hemoglobin per red blood cell (mean corpuscular hemoglobin content, or MCH), and the amount of hemoglobin relative to the size of the cell (mean corpuscular hemoglobin concentration, or MCHC) in more than 14,000 healthy individuals from Europe. They found sixteen new genetic associations with blood traits from fifteen genomic regions not previously thought to be involved.
<a href="https://dx.doi.org/10.1038/ng.466">Santhi Ganesh and her colleagues in the CHARGE consortium</a> measured Hb, MCV, RBC, MCH, MCHC, and the percent of red blood cells in whole blood (hematocrit, or Hct) in more than 24,000 Caucasian individuals from the U.S. and Europe. Here, they found nine new associated variants from eleven previously unassociated genomic regions.
One of the advantages of these studies is the number of traits that they analyzed.
“Until now, few genome-wide association studies have looked beyond single traits,” said co-author Christian Geiger. “But, through a systematic analysis of correlated traits we can begin to discover such shared genetic variants, forming the basis for understanding how these processes interact to influence health and disease.”
<h6>Coronary Artery Disease</h6>
Both teams noted several genomic regions that play a broad role in blood-related health. The HBS1L-MYB, TFR2-EPO, TMPRSS6 and HFE regions were all associated with at least three different traits. These regions have also been connected to fetal hemoglobin levels. They&#8217;re also connected to the iron-overload condition hemochromatosis. Of these newly associated variants, many are close to genes that present promising candidates for further research.
Soranzo’s team went further by investigating whether two of the variants associated with increased platelet volume (PLT) were also associated with coronary artery disease. They analyzed these SNPs in about 9,500 people with coronary artery disease and 10,500 healthy controls. They found that both variants increased odds of coronary artery disease by about 1.15 times.
<h6>Protection from Infection</h6>
When the researchers looked more closely at the region where and are located, they found a block of ten SNPs that tend to be inherited together. They are all associated with increased PLT and risk of coronary artery disease. They also confirmed previous findings from other researchers of association between celiac disease and type 1 diabetes with SNPs in this block.
Data for chimpanzees and multiple human populations point to a relatively recent event in human evolution. This was where the above-mentioned genetic variants swept across European populations. However this was not the case in East Asian or African populations.
The block of SNPs is located in an area of the genome involved in immune response. The authors suggest that these mutations may have given some populations a survival advantage against infection, despite increasing the risk for certain diseases.

Two Large Studies Identify More Variants Associated with Blood-Related Traits

<img loading="lazy" decoding="async" class="alignright size-full wp-image-5157" title="migraine" src="https://blog-api.23andme.com/wp-content/uploads/2009/10/migraine.jpg" alt="migraine" width="354" height="252" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/10/migraine.jpg 435w, https://blogcms.23andme.com/wp-content/uploads/2009/10/migraine-300x214.jpg 300w" sizes="auto, (max-width: 354px) 100vw, 354px" />
Here’s how it goes for me: a few afternoons a year, usually when I haven’t slept or eaten right, but sometimes for no apparent reason, I begin to sense a pressure behind my left eyebrow and to feel queasy.
<h6>Migraines</h6>
By now I know what’s coming, and I resign myself to another miserable evening and a coming day or two lost to indistinctness. I rush home and secrete myself in the coolest, darkest spot I can find, because for each of my senses the volume seems to have been cranked to amphitheater-level. I lie there for four or five hours, a dog on a leash, thinking grim thoughts and, despite myself, yelping every now and again when the pain ratchets up.
Perhaps you know somebody with migraine and are familiar with the vocabulary they use to capture the experience: &#8216;throbbing&#8217;, &#8216;nauseating&#8217;, &#8216;excruciating&#8217; and the like. All true.  Respite comes only when my stomach has had too much and returns my lunch –  normally one wants to avoid this outcome, but here I welcome it, court it even, which I&#8217;ve always found darkly funny. Then I fall into a dreamless sleep. While some don’t have it as bad as me, many have it far worse.
<h6>New Migraine Headache Survey</h6>
With the launch of our new migraine headache survey today, we at 23andMe invite you all to share your headache experiences, whether you&#8217;re one of the lucky few who&#8217;s never had even a little one or someone who must deal with the threat of migraine pain on a daily basis.  
You needn&#8217;t be a 23andMe customer to take the survey (although we recommend it). All you need is a <a title="Link to Free 23andMe Account Signup" href="https://www.23andme.com/user/signup/" target="_blank" rel="noopener">free 23andMe account</a>.

Migraine headaches are nasty things.
The common feature is a terrible pulsing pain emanating from inside the skull, usually just on one side, but apart from this everyone experiences them a bit differently. Some unlucky folks get them every day, while others get them just once a year. Migraines can last for a few hours or can pound on for days at a time. Then there is the menagerie of symptoms that can accompany the headaches, including nausea, vomiting, visual or aural illusions, and aversion to light, smell, touch and/or sound.
Perhaps most variable across people are the causes of the headache, or triggers. For one person the triggers might be red wine or nuts, for another they might be stress, bright lights, or noise.
There is a wide array of treatment options for migraine. With guidance from their doctors, most migraine sufferers nowadays are able to find partial or full relief from their headaches. Despite the effectiveness of these treatments, the basic biology of the disease is not well-understood1,  and migraine continues to exact a tremendous physical and economic toll on our society2.
<h6>More Research Needed</h6>
Two prominent migraine researchers <a title="Shapiro RE &amp; Goadsby PJ, Cephalalgia (2007)" href="https://www.ncbi.nlm.nih.gov/pubmed/17727471" target="_blank" rel="noopener">have suggested</a> that the blame for the slow progress in understanding migraine lies with a systemic lack of public funding for migraine research. They argue that the relatively recent, and incomplete, acceptance of migraine by the medical and research communities as a genuine medical problem, as opposed to mere melodrama, has led migraine&#8217;s funding to lag well behind that for diseases of similar impact. For example, they estimate that while $13.80 is spent for each sufferer of asthma, just  36 cents of federal research funds are spent per migraine sufferer.
The genetics of migraine are also only partially understood.
That&#8217;s where our new survey comes in. Our community-based research program  <a title="Link to 23andWe Summary Page" href="https://www.23andme.com/research/" target="_blank" rel="noopener">23andWe</a> seeks to empower the public to engage in genetic research from the ground up. We know our efforts cannot substitute for proper federal support of migraine research, but evidence of great public interest, plus a new finding or two, would add to our understanding of the disease and potentially send a message to Washington.
With all haste, then, please head over to the new migraine survey and be counted!
 
Footnotes:
<ol>
<li>What is understood of its biology and chemistry is fascinating, and summarized well  <a title="&quot;Why Migraines Strike&quot;, by Dodick &amp; Gargus, Scientific American 2008" href="http://www.scientificamerican.com/article.cfm?id=why-migraines-strike" target="_blank" rel="noopener">here</a>.</li>
<li>Nearly 40 million people in the US, and a similar number in Europe, suffer from migraine, roughly one in every ten people. Migraine occurs in women about three times more commonly than in men. Migraine is estimated to cost  around <a href="https://www.ncbi.nlm.nih.gov/pubmed/18070057" target="_blank" rel="noopener">$23BN/year in the US </a>and <a href="https://www.ncbi.nlm.nih.gov/pubmed/17727472" target="_blank" rel="noopener">Euro27BN/year in Europe</a> in direct medical costs and in <a href="https://www.ncbi.nlm.nih.gov/pubmed/17426520" target="_blank" rel="noopener">indirect costs</a>, such as lost productivity.</li>
</ol>
 


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23and ¡Mi Cabeza!: A New Migraine Headache Survey

<img loading="lazy" decoding="async" class="alignright size-full wp-image-5081" title="iStock_000009029824XSmall" src="https://blog-api.23andme.com/wp-content/uploads/2009/10/iStock_000009029824XSmall.jpg" alt="iStock_000009029824XSmall" width="300" height="198">
The Near East — a swath of land that encompasses the Arabian Peninsula, the Levant, and everywhere in between — has been populated by humans longer than anywhere else in the world save Africa. It is where agriculture was born and spread into Eurasia. It is where the ancient civilizations of Mesopotamia and Egypt evolved and flourished. And it is where a particular paternal haplogroup, J1e, arose about 10,000 years ago.
<h6>Fathers and Sons</h6>
Paternal haplogroups define a person&#8217;s all-male ancestry (i.e. the origins of your father’s father’s father, etc.), and are passed down from father to son via the Y chromosome. Haplogroup J1e has long interested experts because it seems to have expanded and flourished in the harsh deserts of Arabia.
Today it is quite common among Bedouin nomads from Saudi Arabia, United Arab Emirates, and Oman, as well as in men from Turkey, Ethiopia, and the Levant.
<h6>Nomads</h6>
In 2008, scientists at Stanford University proposed that the presence of J1e throughout the Near East could be tied to the nomadic hunter-herders who have dotted the region for thousands of years.
In the October 14 issue of the <a href="https://www.nature.com/ejhg/journal/vaop/ncurrent/abs/ejhg2009166a.html">European Journal of Human Genetics</a>, these same scientists — including 23andMe consultants Roy King and Peter Underhill and 23andMe scientist Brenna Henn — test this theory with a little help from the field of linguistics.

The authors analyzed the DNA of more than 500 men from nearly 40 locations throughout the Near East.
While many of these men belonged to haplogroup J1e, there were small genetic variations within J1e based on exactly where these men lived. For example, J1e samples from Turkey were slightly different from those in Oman.
<h6>A Connection to Language</h6>
When the authors examined differences among the ancient peoples of the Near East, they discovered that the languages spoken in different parts of the region were quite distinct. Until the Arabic swept across the Near East more than 1,000 years ago, there were dozens of languages spoken in the region. These include languages such as Aramaic in Syria, Babylonian in Iraq, and Canaanite from Lebanon to Jordan. The majority of these tongues are now extinct. However, all belong to the same Semitic language family, to which Hebrew and Arabic also belong.
The authors reasoned that the history of these ancient languages may be tied to the people who spoke them. The history of these ancient people could be deciphered further by examining their genetic ancestry via paternal haplogroup J1e.
The researchers&#8217; combined analysis of the J1e types and the ancient Semitic languages revealed some startling results. The authors found that J1e arose in Anatolia (present-day Turkey). Then about 10,000 years ago they expanded southward toward Arabia.
<h6>Semitic Langauges</h6>
Limited archaeological evidence supports such an expansion. Hunter-gatherer groups, using bow-and-arrow technology and with the help of domesticated dogs, headed south into the heart of the Near East. Soon after they began expanding, the hunter-gatherers took up herding, domesticating animals like cattle and goats.
The linguistic evidence lends additional support. The common ancestor of all Semitic languages, called proto-Semitic, originated about 7,500 years ago. This corresponds with when J1e was expanding. More importantly, the spread of proto-Semitic coincides with the spread of hunter-herders across the Near East.
So what does all this mean?
The expansion of haplogroup J1e is closely tied to the expansion of the Semitic languages. And they are both linked to the expansion of hunter-herders. It was hunter-herders who journeyed from Anatolia southward into Arabia thousands of years ago. We now know just a little bit more about the ancient history of this fascinating region.

Linguistics Key to History of Paternal Haplogroup J1e

<img loading="lazy" decoding="async" class="alignright size-full wp-image-3114" title="bloodcells" src="https://blog-api.23andme.com/wp-content/uploads/2009/03/bloodcells.jpg" alt="bloodcells" width="290" height="215" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/03/bloodcells.jpg 350w, https://blogcms.23andme.com/wp-content/uploads/2009/03/bloodcells-300x223.jpg 300w" sizes="auto, (max-width: 290px) 100vw, 290px" />
Doctors routinely order the complete blood count (CBC) for their patients because they can learn a lot about a person&#8217;s health by measuring the numbers of different types of blood cells in the circulation, their sizes and the ratios between them.
One component of the CBC is usually a measure of the total amount of hemoglobin, the oxygen carrying protein found in red blood cells.   Low levels of hemoglobin can be a sign of nutritional deficiency, autoimmune disease or bone marrow problems, and may result in fatigue, irregular heartbeat and poor growth in children.   Abnormally high levels of hemoglobin can be caused by heart failure, COPD or kidney cancer and are associated with increased risk of stroke.
New research published online in the journal <a href="https://dx.doi.org/10.1038/ng.462" target="_blank" rel="noopener noreferrer">Nature Genetics</a> this week identifies two SNPs that account for a small amount of the variation in hemoglobin levels seen in the population and may help scientists find new ways to treat blood disorders.
John Chambers and colleagues analyzed the DNA from more than 11,000 Europeans in England and Finland and more than 16,000 Indian Asians living in London.   They found and both impacted hemoglobin levels.
In both the European and Indian study groups, each A at and each G at led to an approximately 0.1 gram per deciliter (g/dL) decrease in hemoglobin levels. The normal range for hemoglobin levels in adults is 12 to 18 g/dL.
Approximately 25% of the world&#8217;s population has hemoglobin levels low enough to be considered anemic.   The <a href="http://www.who.int/nutrition/publications/micronutrients/anaemia_iron_deficiency/9789241596657/en/index.html" target="_blank" rel="noopener noreferrer">World Health Organization</a> has deemed anemia a severe public health problem in India.   Although nutritional iron deficiencies are a large part of the problem in this and other countries with high levels of anemia, it is interesting to note that the versions of and that lead to lower hemoglobin levels were found at higher frequencies in the Indian study subjects.
Both SNPs identified in this study are in or near genes involved in regulating the body&#8217;s iron levels. One of the SNPs is near the HFE gene.   Mutations in this gene cause hereditary hemochromatosis, a condition that can result in iron overload.   The researchers found, however, that the effect of is not related to these mutations. Another SNP is located in the TMPRSS6 gene.   Mutations in this gene have been shown to cause a serious form of anemia that does not respond to treatment with oral iron supplements.   Chambers says that learning more about how this gene contributes to hemoglobin levels could lead to new treatments for people suffering from chronic hemoglobin problems.
&#8220;The enzyme protein produced by the TMPRSS6 gene is a good target for drug development. Designing a drug that enhances TMPRSS6 activity could augment hemoglobin in people such as cancer and kidney failure patients, who suffer from chronically low levels. A different drug that blocked TMPRSS6 enzyme production might bring down high hemoglobin levels,&#8221; he said in a statement.
Several other reports published online this week in Nature Genetics (<a href="https://dx.doi.org/10.1038/ng.456" target="_blank" rel="noopener noreferrer">Benyamin et al.</a>, <a href="https://dx.doi.org/10.1038/ng.467" target="_blank" rel="noopener noreferrer">Soranzo et al.</a> and <a href="https://dx.doi.org/10.1038/ng.466" target="_blank" rel="noopener noreferrer">Ganesh et al.</a>) also examined genetic contributions to blood traits.   These will be covered later this week here in the Blog.   Benyamin et al. and Ganesh et al. also both found evidence for an association between and hemoglobin concentration.

Genetic Variations Influencing Hemoglobin Levels Identified

<img loading="lazy" decoding="async" class="alignright size-full wp-image-5013" title="dnaoragami" src="https://blog-api.23andme.com/wp-content/uploads/2009/10/dnaoragami.jpg" alt="dnaoragami" width="340" height="226" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/10/dnaoragami.jpg 400w, https://blogcms.23andme.com/wp-content/uploads/2009/10/dnaoragami-300x200.jpg 300w" sizes="auto, (max-width: 340px) 100vw, 340px" />A segment of chromosome 14 folded to reveal a fractal curve using Origami. Designed and folded by Jason Ku. Photo by Erik Demaine. 
How do you get three billion pairs of As, Cs, Ts and Gs–about six feet worth of DNA–into the nucleus of a tiny cell?
Most students of biology would answer by saying that this is accomplished by tightly coiling up the DNA.
Oh yeah?
Well, how is it coiled?
<h6>Tighten Up</h6>
As cells perform different functions and respond to different environmental signals, proteins that help turn genes on and off need to quickly gain access to different parts of the genome.   That means DNA needs to be arranged in such a way that it won&#8217;t get all tangled up.
Packing DNA like luggage at the end of a vacation, with everything smashed together and shoved in any which way, just won&#8217;t cut it.
<h6>Hi-C</h6>
Using a new technique called &#8220;Hi-C,&#8221; researchers at Harvard, MIT and the University of Massachusetts appear to have solved the riddle. Their results, published today in the journal <a href="https://dx.doi.org/10.1126/science.1181369" target="_blank" rel="noopener noreferrer">Science</a>, show that nature has devised quite an elegant storage solution.
<img loading="lazy" decoding="async" class="alignleft size-full wp-image-5055" title="globules2" src="https://blog-api.23andme.com/wp-content/uploads/2009/10/globules2.jpg" alt="globules2" width="258" height="508" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/10/globules2.jpg 258w, https://blogcms.23andme.com/wp-content/uploads/2009/10/globules2-152x300.jpg 152w" sizes="auto, (max-width: 258px) 100vw, 258px" />Equilibrium (top) and fractal (bottom) globules. Nearby regions on a chain of DNA are indicated using similar colors. The equilibrium globule is highly entangled; regions nearby along the chain are far apart in 3D. In the fractal globule, regions nearby along the chain are also nearby in 3D. Images: Leonid A. Mirny and Maxim Imakaev 
The scientists first treated cells with formaldehyde to freeze the DNA in place.   They then used enzymes to break the DNA apart and put it back together in a different configuration.
A final step of sequencing allowed them to identify pieces of DNA that are naturally close together in the nucleus.
&#8220;We made a fantastic three-dimensional jigsaw puzzle and then, with a computer, solved the puzzle,&#8221; said co-first author Nynke van Berkum in a statement.
Two important aspects of DNA organization emerged.   First, there are two main compartments in the nucleus — one for DNA that is in use and one that acts as a storage facility for unneeded sequences.
&#8220;Cells cleverly separate the most active genes into their own special neighborhood, to make it easier for proteins and other regulators to reach them,&#8221; said one of the paper&#8217;s senior authors, Job Dekker of UMass Medical School, in a statement.
<h6>Globule of Globules</h6>
The other striking aspect of the nucleus is that chromosomes appear to be folded up into an arrangement called a fractal globule, which the authors described as a &#8220;beads-on-a-string&#8221; configuration.   Multiple rounds of &#8220;crumpling&#8221; of the DNA into beads leads to a &#8220;globule-of-globules-of-globules.&#8221;
Previous models suggested that DNA was in a more random arrangement called an equilibrium globule.   This configuration, however, is known to be prone to dense knotting.   Fractal globules are knot-free.
Image Source: Harvard School of Engineering and Applied Sciences

Research Reveals How Our Cells Pack in All That DNA

<img loading="lazy" decoding="async" class="alignright size-full wp-image-4987" title="alexandraandalexei" src="https://blog-api.23andme.com/wp-content/uploads/2009/10/alexandraandalexei.jpg" alt="alexandraandalexei" width="350" height="347" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/10/alexandraandalexei.jpg 350w, https://blogcms.23andme.com/wp-content/uploads/2009/10/alexandraandalexei-150x150.jpg 150w, https://blogcms.23andme.com/wp-content/uploads/2009/10/alexandraandalexei-300x297.jpg 300w" sizes="auto, (max-width: 350px) 100vw, 350px" /> 
Empress Alexandra Feodorovna and Prince Alexei, 1911.
Editor&#8217;s note: June 4, 2024, This post has been updated.
From the <a href="https://blog.23andme.com/articles/inbreeding-doomed-habsburg">Habsburgs of Austria</a> to the Romanovs of Russia, the quest for maintaining &#8220;pure&#8221; bloodlines has often haunted royal dynasties throughout history. The princes of early 20th-century Europe were no exception.
The source of their wealth and power &#8212; the royal blood coursing through their veins &#8212; could also sentence them to an early death.
<h2>Blood Disorder</h2>
A mutation that spontaneously arose in the DNA of Britain&#8217;s Queen Victoria doomed many of her male descendants to the bleeding disorder known as hemophilia. The mutation is known to have been on one of her X chromosomes, but because it didn&#8217;t last beyond the fourth generation, scientists have never been able to tell which type of hemophilia plagued the princes of Europe.
Now researchers studying the remains of the Romanovs, the Russian royals killed at the start of the Bolshevik revolution, appear to have finally identified the &#8220;<a href="https://www.23andme.com/gen101/variation/hemophilia/" target="_blank" rel="noopener">royal disease</a>.&#8221;
<h2>The Romanovs</h2>
Empress Alexandra, wife of Emperor Nicholas and granddaughter of Queen Victoria, is known to have been a carrier for the royal hemophilia mutation because her son, Crown Prince Alexei, was afflicted with the disease.
By analyzing the X chromosome DNA in Alexandra&#8217;s remains, Evgeny Rogaev and colleagues uncovered a tiny, single-base DNA change in the gene that encodes factor IX, an essential blood-clotting protein.
This result, published online today in <a href="http://www.sciencemag.org/cgi/content/abstract/sci;1180660v1?maxtoshow=&amp;HITS=10&amp;hits=10&amp;RESULTFORMAT=&amp;fulltext=royal+disease&amp;searchid=1&amp;FIRSTINDEX=0&amp;resourcetype=HWCIT" target="_blank" rel="noopener">Science Express</a>, indicates that the royal families of Europe suffered from <a href="http://www.nlm.nih.gov/medlineplus/ency/article/000539.htm" target="_blank" rel="noopener">hemophilia B</a>.   This form of the disease is about seven times less common than classic hemophilia (also called <a href="http://www.nlm.nih.gov/medlineplus/ency/article/000538.htm" target="_blank" rel="noopener">hemophilia A</a>), which is caused by mutations in the gene that encodes another clotting protein, factor VIII.
<h2>Alexi&#8217;s DNA</h2>
As expected, when the researchers looked at Alexei&#8217;s DNA, they found that his X chromosome contained the factor IX mutation.   DNA from remains presumed to be from Grand Duchess Anastasia also showed evidence of this factor IX mutation, meaning that, like her mother, she was a carrier for hemophilia.   Had this young girl really escaped execution, as was <a href="https://blog.23andme.com/2009/02/24/historys-mysteries-finding-answers-in-our-dna/" target="_blank" rel="noopener">rumored for many years</a>, any sons she had would have each had a 50% chance of continuing on the tradition of the royal disease.
Image: Permission of the State Archives of the Russian Federation

Researchers Discover the True Identity of the “Royal Disease”

<img loading="lazy" decoding="async" class="alignright size-full wp-image-2057" title="DNA Strand" src="https://blog-api.23andme.com/wp-content/uploads/2008/11/istock_000000628100xsmall.jpg" alt="DNA Strand" width="334" height="250" srcset="https://blogcms.23andme.com/wp-content/uploads/2008/11/istock_000000628100xsmall.jpg 400w, https://blogcms.23andme.com/wp-content/uploads/2008/11/istock_000000628100xsmall-300x225.jpg 300w" sizes="auto, (max-width: 334px) 100vw, 334px" />
Dan Vorhaus at <a href="http://www.genomicslawreport.com/" target="_blank" rel="noopener">Genomics Law Report</a> has launched &#8220;What ELSI is new?&#8221;, a series of guest posts on the most pressing ethical, legal, and social issues (ELSI) relating to genomics.   (You gotta love the name.)   The contributor list is a who&#8217;s who of voices in the ELSI, policy, and blog worlds.   I&#8217;m honored to be representing 23andMe in the discussion; my own post will appear next Tuesday.
<a href="http://www.genomicslawreport.com/index.php/2009/10/05/how-will-we-handle-the-rapidly-approaching-flood-of-genomic-information-on-individual-patients-and-consumers/" target="_blank" rel="noopener">Today&#8217;s post</a> is by Prof. Hank Greely, with whom I had the pleasure of serving on a panel at the Stanford Genetics departmental retreat a few weeks ago.   He makes the important point that trained genetics professionals are too few and far between to expect consultations for every genomics consumer, especially when sequence information is getting cheaper and cheaper.   What&#8217;s the right response: to restrict access to genetic information because of the danger of misinterpretation, or to accept the risk but mitigate it as well as possible through education?

“What ELSI is new?” at Genomics Law Report

<img loading="lazy" decoding="async" class="alignright size-full wp-image-4950" title="iStock_000004898479XSmall" src="https://blog-api.23andme.com/wp-content/uploads/2009/10/iStock_000004898479XSmall.jpg" alt="iStock_000004898479XSmall" width="347" height="346" srcset="https://blogcms.23andme.com/wp-content/uploads/2009/10/iStock_000004898479XSmall.jpg 347w, https://blogcms.23andme.com/wp-content/uploads/2009/10/iStock_000004898479XSmall-150x150.jpg 150w, https://blogcms.23andme.com/wp-content/uploads/2009/10/iStock_000004898479XSmall-300x300.jpg 300w, https://blogcms.23andme.com/wp-content/uploads/2009/10/iStock_000004898479XSmall-271x271.jpg 271w" sizes="auto, (max-width: 347px) 100vw, 347px" />
Our bones are amazing structures, capable of supporting tremendous force through complex motions. They do this day in and day out, year after year as we sit, stand, walk, run, lift, work, and play. But as the elderly among us know all too well, bones are not invincible and <a href="http://www.mayoclinic.com/health/osteoporosis/DS00128/DSECTION=causes">become more fragile as we age</a>. As the natural, continuous cycle of bone turnover slows down and becomes unbalanced, bone is broken down faster than it is replaced &#8212; and important bone-strengthening minerals like calcium are lost.
Low <a href="http://www.webmd.com/osteoporosis/bone-mineral-density">bone mineral density</a> (BMD) is one of the hallmarks of osteoporosis (literally &#8220;porous bones&#8221;), a disease that <a href="http://www.niams.nih.gov/Health_Info/Bone/Osteoporosis/default.asp">impacts</a> nearly 45 million people in US and is responsible for more than one million fractures each year. Women develop osteoporosis much more frequently than men, especially after menopause. The burden on the health care system is significant and is expected to double over the next 10-15 years as the population ages.
Although it is natural to lose bone mass as we get older, genetic factors are known to play a large role in determining bone mass and the rate at which bone mineral density decreases. The relationship between genetics and BMD is complex, and association studies have implicated many different genes that may play a role. New research published this week in <a href="https://dx.doi.org/10.1038/ng.446">Nature Genetics</a> continues the search for genetic factors and has identified more than a dozen SNPs associated with BMD in Europeans.
The team of researchers, led by Fernando Rivadeneira and Andre Uitterlinden of the Erasmus Medical Center in The Netherlands, used data from the Genetic Factors for Osteoporosis (<a href="http://www.gefos.org/">GEFOS</a>) Consortium containing lumbar spine BMD and femoral neck BMD measurements for almost 20,000 individuals. About half of the variants they identified replicated previously reported genetic associations with BMD, but the other half were new.
Some of the SNPs were associated with lower BMD while others were associated with higher BMD. For instance, individuals with one or more copies of the C allele at one of the SNPs tended to have lower lumbar spine BMD than those without, and individuals with one or more copies of the C allele at another SNP tended to have higher lumbar and femoral neck BMD.
The exact biological processes affected by these variants are still unclear, but increasing evidence points to several signaling pathways known to be important in bone biology.
One of these pathways is mediated by the &#8220;Wnt&#8221; family of proteins; <a href="http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&amp;pubmedid=18164181">Wnt signaling</a> is important both for proper differentiation of cells responsible for breaking down bone and for the development of cartilage, required for new bone formation. , for instance, is near the gene that encodes Î²-catenin, an important node through which Wnt proteins influence cellular processes such as gene expression (this SNP is not on 23andMe&#8217;s platform but correlates perfectly with one that is, ). Wnt proteins can also act through other channels potentially affected by additional SNPs identified by this study.
Another pathway implicated by the growing body of research is estrogen signaling. There is no doubt that the drop in estrogen following menopause in women leads to increased risk for osteoporosis, and hormone replacement therapy can have a protective effect. Not surprisingly, estrogen affects numerous biological processes &#8211; including bone maintenance &#8211; mainly through its role in gene expression. <a href="http://aje.oxfordjournals.org/cgi/content/full/161/4/307">Variants in ESR1</a>, the major estrogen receptor found in bone, have been associated with BMD and osteoporosis, though <a href="http://jmg.bmj.com/cgi/content/short/42/3/240">results are far from conclusive</a>. Rivadeneira and colleagues confirmed the association of a SNP in ESR1, , with lumbar spine BMD. Several other SNPs are also located in or near genes that may influence the regulation of bone development.
Osteoporosis is the most common bone disorder in developed countries. One in two women and one in four men over the age of 50 will experience a bone fracture due to the disease. Diets rich in calcium (especially before your mid-30s) and regular exercise can help combat bone loss. Meanwhile, the search carries on for clues that could lead to greater understanding of bone disease and potential avenues for treatment.

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