Large genome-wide association study (GWAS) identifies protein-altering variants associated with BMI and energy intake, in obesity

Obesity is an inherited multifactorial trait –– which reflects the contribution of genetics (DNA sequence variants), epigenetic factors (DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling), plus environmental effects (diet, lifestyle, in utero environment during the pregnancy, drug-drug interactions, chronic diseases, etc.). Genome-wide association studies (GWAS) for body-mass index (BMI) and obesity risk, over the past decade, have identified more than 250 common variants. Tissue expression and gene set enrichment analyses for genes implicated in BMI-associated loci have shown that the central nervous system (CNS) plays a critical role in body weight regulation. Whereas numerous GWAS-loci have provided insight into broad biological mechanisms underlying body weight regulation, pinpointing the causal gene(s) and variant(s) remains a major challenge, because GWAS-identified variants are typically noncoding and may affect genes at long distances from the identified DNA variant nucleotide.

The association of intronic FTO variants with BMI –– is a great example of the challenges of identifying causal regulatory effects. The proposed causal variant in this locus was found to regulate expression of nearby RPGRIP1L in some studies, whereas others found that it regulated the distant IRX3 and IRX5 genes in specific cell types. Authors [see attached] performed whole-exome sequencing (WES) to search for low-frequency (minor allele frequency; MAF = 1–5%) and rare (MAF <1%) single-nucleotide variants (SNVs) associated with BMI. A meta-analysis of 125 studies (N = 718,734) included single-variant associations between 246,000+ SNVs and BMI. In addition, authors performed gene-based meta-analyses to aggregate rare and low-frequency coding SNVs across 14,541 genes. Using genetic, functional and computational follow-up analyses, authors gained insights into the function of BMI-implicated genes and the biological pathways through which they might influence body weight. Authors identified 14 coding variants in 13 genes, of which eight variants were in genes newly implicated in obesity (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169), two variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity, and two variants were in GIPR. (gastric inhibitory polypeptide receptor). The effect-sizes of rare variants were ~10 times larger than those of common variants, with the largest effect observed in carriers (who weighed ~7 kg more than non-carriers) of an MC4R mutation (melanocortin-4 receptor). Pathway analyses –– based on the variants associated with BMI –– confirm enrichment of neuronal genes and provide new evidence for adipocyte (fat cell) and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity. Nat Genet Jan 2o18; 50: 26–41

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