Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Abstract

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Influence of TFAP2B and KCTD15 genetic variability on personality dimensions in anorexia and bulimia nervosa

“…(2010), who failed to find a significant effect of a KCTD15 polymorphism previously associated with obesity in AN patients; as well as with several GWAS, which have not identified any KCTD15 SNP related to AN risk (Boraska et al., 2014; Hinney et al., 2017; Wang et al., 2011). In this regard, several loci in or near KCTD15 have repeatedly been associated with obesity in a number of GWAS and replication studies (Mei et al., 2012; Paternoster et al., 2011; Thorleifsson et al., 2009; Willer et al., 2009). The cerebral location of the gene indicates that its association with weight increase would likely be based on changes in feeding behavior.…”

“…The analysis of obese patients in our sample could confirm that KCTD15 and TFAP2B variants may be related to obesity risk, a finding that has also been suggested by a number of GWAS and replication studies (Albuquerque et al., 2014; Bauer et al., 2009; Lv et al., 2015; Willer et al., 2009). Moreover, the genetic profile of AN, BN and obese patients did not differ significantly, only rs2817420 was differently distributed between the groups.…”

“…A number of GWAS have identified SNPs in or near de KCTD15 gene as putative regulators of body mass index (BMI) (Mei et al., 2012; Paternoster et al., 2011; Thorleifsson et al., 2009; Willer et al., 2009). Interestingly, there is recent evidence in animal models that TFAP2B and KCTD15 homologues co‐localize in areas of the brain where they interact to regulate feeding behavior and reward (Williams et al., 2014) (Figure 1).…”

Genetics of Taste and Smell

“…51-54 However, a direct relationship between TAS2R38 genotype, food intake, and body weight has not been detected in epidemiological studies 55,56 or in genome-wide studies of association with body mass index, a measure of obesity. 10,57,58 Thus, if alleles of this bitter receptor gene can directly affect food intake or body weight, they are too weak to be detected in the population as a group. Progress toward understanding genotype/phenotype relationships for PTC taste-blindness and food intake will require narrowing the focus to vegetables that contain these specific compounds.…”

Meta-analysis of SNPs involved in variance heterogeneity using Levene’s test for equal variances

“…gene, which is known to be associated with BMI 16 and severe obesity in a pediatric cohort, 5 was in weak LD (r 2 ¼ 0.325; D' ¼ 0.888; Distance ¼ 231.44 kb) with rs12132044 and also nominally significant for variance heterogeneity (P ¼ 0.0076). None of the other top hits for log(BMI) or log(height) were correlated with variants associated with other traits or diseases in their neighboring regions (Supplementary Table S2).…”