Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

Abstract

Obesity is globally prevalent and highly heritable, but the underlying genetic factors remain largely elusive. To identify genetic loci for obesity-susceptibility, we examined associations between body mass index (BMI) and ~2.8 million SNPs in up to 123,865 individuals, with targeted follow-up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity-susceptibility loci and identified 18 new loci associated with BMI (P<5×10−8), one of which includes a copy number variant near GPRC5B. Some loci (MC4R, POMC, SH2B1, BDNF) map near key hypothalamic regulators of energy balance, and one is near GIPR, an incretin receptor. Furthermore, genes in other newly-associated loci may provide novel insights into human body weight regulation.

Genomewide meta‐analysis identifies loci associated with IGF ‐I and IGFBP ‐3 levels with impact on age‐related traits

“…We also examined the associations of the IGF‐I‐ and IGFBP‐3‐associated SNPs with anthropometric traits (height, BMI, waist‐to‐hip ratio, and fat percentage) (Heid et al ., 2010; Lango Allen et al ., 2010; Speliotes et al ., 2010), bone mineral density (Estrada et al ., 2012), risk of type 2 diabetes (Voight et al ., 2010; Morris et al ., 2012) and related traits (fasting glucose, 2‐h glucose, HbA1c, fasting insulin, proinsulin, HOMA‐IR, and HOMA‐B) (Dupuis et al ., 2010; Saxena et al ., 2010; Soranzo et al ., 2010), and coronary artery disease (Coronary Artery Disease Genetics C, 2011; Schunkert et al ., 2011; Consortium CAD and Deloukas, 2013) (Table S9, Supporting information). Many nominal associations were expected because of the known influence of the IGF system on these traits.…”

“…Top SNPs associated with levels of IGF‐I and IGFBP‐3 were examined in relationship to other phenotypes using published data on serum metabolites (Suhre et al ., 2011; Shin et al ., 2014), anthropometric traits (Heid et al ., 2010; Lango Allen et al ., 2010; Speliotes et al ., 2010), bone mineral density (Estrada et al ., 2012), diabetes (Voight et al ., 2010; Morris et al ., 2012) and glycemic traits (Dupuis et al ., 2010; Saxena et al ., 2010; Soranzo et al ., 2010), coronary artery disease (Coronary Artery Disease Genetics C, 2011; Schunkert et al ., 2011; Consortium CAD and Deloukas, 2013), and survival beyond 90 years (Broer et al ., 2015). Detailed information of the published datasets used including its references is given in Table S9 (Supporting information).…”

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…Among those, SH2B1 encodes a Src homology adaptor protein involved in leptin and insulin signaling. 25,26 Common variants near this locus are associated with BMI, serum leptin, and body fat in genome-wide association studies (GWASs), [27][28][29][30] while rare dominant mutations have been reported to cause obesity, social isolation, aggressive behavior, and speech and language delay. 31 None of the CNV-contained genes have been associated with ASD or HC defects.…”

Joint association analysis of a binary and a quantitative trait in family samples

“…24 Among the remaining top 20 SNVs, chromosome 16 SNVs (rs8059849, rs9931529, rs13332434, rs9783765) are near FTO, a gene known for its association with both BMI and T2D. [24][25][26][27][28][29] The SNV rs10894188 (chromosome 11) is near MTNR1B, a gene known to be associated with both T2D and obesity-related traits; 26 rs12097783 (chromosome 1) is near previously identified BMI gene SEC16B; [29][30][31][32] rs11145958 (chromosome 9) is near GPSM1, a T2D-associated gene; 33 5 SNVs on chromosome 1 are near NOTCH2 25 and ADAM30, 25 two genes known for SNVs associated with T2D; rs17863929 (chromosome 4) is approximately 3 Mb away from IL2, 34 a gene known for SNVs in the intron region associated with type-1 diabetes.…”