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

TitleNRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.
Publication TypeJournal Article
Year of Publication2009
AuthorsHeard-Costa NL, Zillikens CM, 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-D I, 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, L Cupples A, Fox CS, North KE
JournalPLoS Genet
Volume5
Issue6
Paginatione1000539
Date Published2009 Jun
ISSN1553-7404
KeywordsAged, Body Mass Index, Cohort Studies, European Continental Ancestry Group, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Nerve Tissue Proteins, Obesity, Polymorphism, Single Nucleotide, Waist Circumference
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.

DOI10.1371/journal.pgen.1000539
Alternate JournalPLoS Genet
PubMed ID19557197
PubMed Central IDPMC2695005
Grant ListN01HC55020 / HL / NHLBI NIH HHS / United States
M01-RR00425 / RR / NCRR NIH HHS / United States
N02-HL-6-4278 / HL / NHLBI NIH HHS / United States
N01-HC-25195 / HC / NHLBI NIH HHS / United States
P30 DK063491-05 / DK / NIDDK NIH HHS / United States
R01 AR046838 / AR / NIAMS NIH HHS / United States
N01AG12100 / AG / NIA NIH HHS / United States
N01HC55018 / HL / NHLBI NIH HHS / United States
HSN268200625226C / / PHS HHS / United States
R01HL59367 / HL / NHLBI NIH HHS / United States
UL1 RR025005 / RR / NCRR NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
U01 HL72515 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
UL1 RR 025005 / RR / NCRR NIH HHS / United States
R01 HL059367 / HL / NHLBI NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
P30 DK079637 / DK / NIDDK NIH HHS / United States
R01 HL086694 / HL / NHLBI NIH HHS / United States
R01 AG18728 / AG / NIA NIH HHS / United States
R01 HL087652 / HL / NHLBI NIH HHS / United States
U01 HG004402 / HG / NHGRI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
M01 RR 16500 / RR / NCRR NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-85086 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
N01-HC-15103 / HC / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
R01DK06833603 / DK / NIDDK NIH HHS / United States
U01HG004402 / HG / NHGRI NIH HHS / United States
P30 DK063491-039004 / DK / NIDDK NIH HHS / United States
U01 HL084756 / HL / NHLBI NIH HHS / United States
R01DK07568101 / DK / NIDDK NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
N01 HC-55222 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
R01HL087641 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-75150 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
U01 HL072515 / HL / NHLBI NIH HHS / United States
P30 DK063491-029004 / DK / NIDDK NIH HHS / United States
M01 RR016500 / RR / NCRR NIH HHS / United States
U01 HL84756 / HL / NHLBI NIH HHS / United States
M01 RR000425 / RR / NCRR NIH HHS / United States
R01HL08770003 / HL / NHLBI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
P30 DK063491-019004 / DK / NIDDK NIH HHS / United States
N01HC25195 / HL / NHLBI NIH HHS / United States
DK063491 / DK / NIDDK NIH HHS / United States
N01-HC-85079 / HC / NHLBI NIH HHS / United States
P30 DK063491-049004 / DK / NIDDK NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States
R01 HL087641 / HL / NHLBI NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
R01 AG018728 / AG / NIA NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R01HL086694 / HL / NHLBI NIH HHS / United States
R01 HL088119 / HL / NHLBI NIH HHS / United States