Researchers Find Genetic Variants That May Influence the Risk For Obesity

European researchers have identified variations in the PCSK1 gene that could influence obesity risk in both adults and children. The results, published online in Nature Genetics, are based on data collected from nearly 14,000 people in five European countries.

The team was led by David Meyre and Philippe Froguel of the Pasteur Institute in France, who have been studying the genetics of diabetes and obesity.

The researchers were inspired by the earlier research of British colleagues, who discovered a rare mutation in the PCSK1 gene about a decade ago. That mutation causes obesity by preventing the production of an enzyme involved in metabolism.

For this study, Meyre, Froguel and their colleagues started by examining genetic data from 1,045 obese and 1,265 non-obese French adults. They found six variants — or SNPs — in PCSK1 that showed a strong association with obesity. The researchers narrowed their list to just two SNPs that cause protein sequence changes: rs6232 and rs6234/rs6235. Because the latter two SNPs are linked, they were treated as one variation by the researchers. (23andMe customers should note that while our service does not currently offer information on rs6234 or rs6235, SNP rs10515237 can be used as a direct substitute for this variation.)

An association between obesity and the PCSK1 variants was also observed when the researchers sampled Danish adults, Swiss adults, French children and Swedish families. A sample of children from Germany found an association with SNP rs6232, but not rs6234/rs6235.

After compiling all their data, the researchers found that each copy of the riskier C version of rs6232 increased a person’s odds for obesity 1.34 times over the TT genotype. Each copy of the riskier G version of rs10515237 — which 23andMe uses instead of rs6234/rs6235 — increased odds for obesity 1.22 times over the AA genotype.

In laboratory experiments, the researchers found that while the obesity-associated variants of PCSK1 found in this study do not interfere with production of the enzyme, rs6232 did reduce the enzymatic activity of the PCSK1 protein by 10%. Research in mice has shown that a change in the mouse PCSK1 gene very similar to the C version of rs6232 in humans results in increased fat accumulation and obesity.

In the following table, “Effect” is the increase in odds of developing obesity conferred by each copy of the riskier version of a SNP. SNPs where we are providing a proxy for the ones originally reported in the paper are marked with an asterisk. This information applies only to people with European ancestry.