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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.

SUBMITTER: Heard-Costa NL

PROVIDER: S-EPMC2695005 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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

Heard-Costa Nancy L NL Zillikens M Carola MC Monda Keri L KL Johansson Asa A Harris Tamara B TB Fu Mao M Haritunians Talin T Feitosa Mary F MF Aspelund Thor T Eiriksdottir Gudny G Garcia Melissa M Launer Lenore J LJ Smith Albert V AV Mitchell Braxton D BD McArdle Patrick F PF Shuldiner Alan R AR Bielinski Suzette J SJ Boerwinkle Eric E Brancati Fred F Demerath Ellen W EW Pankow James S JS Arnold Alice M AM Chen Yii-Der Ida YD Glazer Nicole L NL McKnight Barbara B Psaty Bruce M BM Rotter Jerome I JI Amin Najaf N Campbell Harry H Gyllensten Ulf U Pattaro Cristian C Pramstaller Peter P PP Rudan Igor I Struchalin Maksim M Vitart Veronique V Gao Xiaoyi X Kraja Aldi A Province Michael A MA Zhang Qunyuan Q Atwood Larry D LD Dupuis Josée J Hirschhorn Joel N JN Jaquish Cashell E CE O'Donnell Christopher J CJ Vasan Ramachandran S RS White Charles C CC Aulchenko Yurii S YS Estrada Karol K Hofman Albert A Rivadeneira Fernando F Uitterlinden André G AG Witteman Jacqueline C M JC Oostra Ben A BA Kaplan Robert C RC Gudnason Vilmundur V O'Connell Jeffrey R JR Borecki Ingrid B IB van Duijn Cornelia M CM Cupples L Adrienne LA Fox Caroline S CS North Kari E KE

PLoS genetics 20090626 6

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 ...[more]

PMID: 19557197

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Project description:Background and purposePrevious studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.MethodsUsing 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).ResultsThe most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.ConclusionsThis first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

Dataset Information

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

Publications

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

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