NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium

Abstract

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

Figure 1. Regional Association Plot for rs10146997 on chromosome 14 in the stage 1 CHARGE-only analysis.

The color scheme is red for strong linkage disequilibrium (LD; r²≥0.8), orange for moderate LD (r²≥0.5 and <0.8), yellow for weak LD (r²≥0.2 and <0.5) and white for limited or no LD (r²<0.2).

Figure 2. Mean waist circumference by number of risk alleles for FTO, MC4R, and NRXN3.

Bars represent standard errors. The panel on the left represents the distribution of risk alleles in the overall sample.