NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.
Heard-Costa NL., Zillikens MC., Monda KL., Johansson A., Harris TB., Fu M., Haritunians T., Feitosa MF., Aspelund T., Eiriksdottir G., Garcia M., Launer LJ., Smith AV., Mitchell BD., McArdle PF., Shuldiner AR., Bielinski SJ., Boerwinkle E., Brancati F., Demerath EW., Pankow JS., Arnold AM., Chen Y-DI., Glazer NL., McKnight B., Psaty BM., Rotter JI., Amin N., Campbell H., Gyllensten U., Pattaro C., Pramstaller PP., Rudan I., Struchalin M., Vitart V., Gao X., Kraja A., Province MA., Zhang Q., Atwood LD., Dupuis J., Hirschhorn JN., Jaquish CE., O'Donnell CJ., Vasan RS., White CC., Aulchenko YS., Estrada K., Hofman A., Rivadeneira F., Uitterlinden AG., Witteman JCM., Oostra BA., Kaplan RC., Gudnason V., O'Connell JR., Borecki IB., van Duijn CM., Cupples LA., Fox CS., North KE.
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.