NRXN3Is a novel locus for waist circumference: A genome-wide association study from the CHARGE consortium

Nancy L. Heard-Costa, M. Carola Zillikens, Keri L. Monda, Åsa Johansson, Tamara B. Harris, Mao Fu, Talin Haritunians, Mary F. Feitosa, Thor Aspelund, Gudny Eiriksdottir, Melissa Garcia, Lenore J. Launer, Albert V. Smith, Braxton D. Mitchell, Patrick F. McArdle, Alan R. Shuldiner, Suzette J. Bielinski, Eric Boerwinkle, Fred Brancati, Ellen W. DemerathJames S. Pankow, Alice M. Arnold, Yii Der Ida Chen, Nicole L. Glazer, Barbara McKnight, Bruce M. Psaty, Jerome I. Rotter, Najaf Amin, Harry Campbell, Ulf Gyllensten, Cristian Pattaro, Peter P. Pramstaller, Igor Rudan, Maksim Struchalin, Veronique Vitart, Xiaoyi Gao, Aldi Kraja, Michael A. Province, Qunyuan Zhang, Larry D. Atwood, Josée Dupuis, Joel N. Hirschhorn, Cashell E. Jaquish, Christopher J. O'Donnell, Ramachandran S. Vasan, Charles C. White, Yurii S. Aulchenko, Karol Estrada, Albert Hofman, Fernando Rivadeneira, André G. Uitterlinden, Jacqueline C.M. Witteman, Ben A. Oostra, Robert C. Kaplan, Vilmundur Gudnason, Jeffrey R. O'Connell, Ingrid B. Borecki, Cornelia M. Van Duijn, L. Adrienne Cupples, Caroline S. Fox, Kari E. North

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222 Scopus citations


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 = 6.4×10 -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 = 5.3×10-8 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 = 7.4×10-6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2×10-5 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.

Original languageEnglish
Article numbere1000539
JournalPLoS genetics
Issue number6
StatePublished - Jun 2009


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