GWAS identifies 112 new loci for body mass index (BMI), and suggesting that lymphocytes are relevant to body weight regulation and obesity …??

Obesity, which appears to be at least in part heritable, is a risk factor for various diseases. Numerous genome-wide association studies (GWAS) have identified more than 100 DNA loci associated with body mass index (BMI) –– the most commonly used measurement for obesity. However, these loci can explain only a fraction (~20%) of heritability [defined as the proportion of total variation among individuals in a given population due to genetic causes; this number can range from 0% (no genetic contribution) to 100% (all differences of a trait reflect genetic variation).] in Europeans. Therefore, most of the genetic components of BMI have not yet been discovered.

Interestingly, whereas most previous studies were individuals of European ancestry, GWAS in non-Europeans have identified different loci. Moreover, epidemiological surveys reported differences in BMI across ethnicities (e.g. the prevalence of obesity is lower in Asians than in Europeans and North Americans. In addition, Asians tend to develop diabetes with a lower BMI than Europeans. These differences suggest that analyzing different populations could yield further insight into the etiology of obesity. In my personal experience of having visited Japan during the past 35+ years, however, the incidence of obesity has exploded during this time period –– as anyone can observe, just by viewing the younger generation walking around the subway stations of Tokyo or a similar city. This suggests to me that –– in addition to DNA-sequence variants –– obviously epigenetic and environmental factors (e.g. Western diet and lifestyle) have helped immensely in causing this dramatic rise in BMI among the Japanese population.

To identify genetic loci associated with obesity and to gain more insight into body weight regulation, authors [see attached study] conducted a GWAS that included >173,430 Japanese volunteers. They then conducted a comprehensive integration with the previous GWAS of Europeans, functional annotations of the associated loci, and genetic correlation analyses between BMI and other complex diseases in humans. Authors found 85 loci significantly associated with obesity (P <5.0 x 10–8), of which 51 were previously unknown. They conducted trans-ancestral meta-analyses –– by integrating these results with results from a GWAS of Europeans and identified 61 additional new loci. In total, this study herein identified 112 novel loci, doubling the number of previously-known BMI-associated loci. By annotating associated variants with cell-type-specific regulatory markers, authors found enrichment of variants in CD19-positive cells (a marker on the surface of B-lymphocytes; a type of white blood cell). They also found significant genetic correlations between BMI and lymphocyte count (P = 6.46 × 10–8; rg = 0.18) and between BMI and multiple complex diseases. These intriguing findings provide genetic evidence –– suggesting that lymphocytes are relevant to body weight regulation, and these data might offer insights into the pathogenesis of obesity. Nature Genetics Oct 2o17; 49: 1458–1467

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