Medical sequencing at the extremes of human body mass

Abstract

Body weight is a quantitative trait with significant heritability in humans. To identify potential genetic contributors to this phenotype, we resequenced the coding exons and splice junctions of 58 genes in 379 obese and 378 lean individuals. Our 96-Mb survey included 21 genes associated with monogenic forms of obesity in humans or mice, as well as 37 genes that function in body weight-related pathways. We found that the monogenic obesity-associated gene group was enriched for rare nonsynonymous variants unique to the obese population compared with the lean population. In addition, computational analysis predicted a greater fraction of deleterious variants within the obese cohort. Together, these data suggest that multiple rare alleles contribute to obesity in the population and provide a medical sequencing-based approach to detect them.

Figure 1.

The percentage of nonsynonymous, synonymous, and intronic variants for different minor-allele frequencies. Percentages and the actual number (N) of variants are written inside the bars of the graph.

Figure 2.

PolyPhen distribution analysis of variants unique to the obese and lean cohorts. Data are presented for genes with evidence of monogenic involvement in obesity (A) and for genes with a biological plausibility for a role in obesity (B). The number of variants is indicated above each bar of the graph. A double asterisk (**) indicates P<.002.

Figure 3.

Familial segregation of MC4R variants and BMI. BMI values are based on the subjects' maximum weight. The arrow indicates the individual sequenced in the cohort. y = years.