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PMID: 19557197 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

PLoS genetics ·Vol. 5 ·No. 6 ·2009-06-00 ·Pages e1000539

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 YD, 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 JC, Oostra BA, Kaplan RC, Gudnason V, O'Connell JR, Borecki IB, van Duijn CM, Cupples LA, Fox CS, North KE

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.

MeSH Terms
Aged Body Mass Index Cohort Studies Female Genetic Predisposition to Disease Genome-Wide Association Study Humans Male Middle Aged Nerve Tissue Proteins/genetics Obesity/genetics Polymorphism, Single Nucleotide Waist Circumference Whites/genetics
Chemicals
Nerve Tissue Proteins neurexin IIIalpha
Authors & Affiliations
61 authors, click to expand affiliations / ORCID
Heard-Costa Nancy L
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Zillikens M Carola
Monda Keri L
Johansson Asa
Harris Tamara B
Fu Mao
Haritunians Talin
Feitosa Mary F
Aspelund Thor
Eiriksdottir Gudny
Garcia Melissa
Launer Lenore J
Smith Albert V
Mitchell Braxton D
McArdle Patrick F
Shuldiner Alan R
Bielinski Suzette J
Boerwinkle Eric
Brancati Fred
Demerath Ellen W
Pankow James S
Arnold Alice M
Chen Yii-Der Ida
Glazer Nicole L
McKnight Barbara
Psaty Bruce M
Rotter Jerome I
Amin Najaf
Campbell Harry
Gyllensten Ulf
Pattaro Cristian
Pramstaller Peter P
Rudan Igor
Struchalin Maksim
Vitart Veronique
Gao Xiaoyi
Kraja Aldi
Province Michael A
Zhang Qunyuan
Atwood Larry D
Dupuis Josée
Hirschhorn Joel N
Jaquish Cashell E
O'Donnell Christopher J
Vasan Ramachandran S
White Charles C
Aulchenko Yurii S
Estrada Karol
Hofman Albert
Rivadeneira Fernando
Uitterlinden André G
Witteman Jacqueline C M
Oostra Ben A
Kaplan Robert C
Gudnason Vilmundur
O'Connell Jeffrey R
Borecki Ingrid B
van Duijn Cornelia M
Cupples L Adrienne
Fox Caroline S
North Kari E
Conflict of Interest

The authors have declared that no competing interests exist.

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Article Info
Journal
PLoS genetics
Abbr.
PLoS Genet
ISSN
1553-7404
DOI
10.1371/journal.pgen.1000539
Published
2009-06-00
Epub
2009-00-26
Pages
e1000539
Language
English
Region
United States
NLM ID
101239074
PMCID
PMC2695005
Subset
IM
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NIDDK NIH HHS · P30 DK063491-05 · United States
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PubMed source DOI: 10.1371/journal.pgen.1000539 PMC Full Text View journal details
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