NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium.
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.
Heard-Costa
Nancy L
NL
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts, United States of America.
Zillikens
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MC
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Johansson
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Tamara B
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BD
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AM
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Yii-Der Ida
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NL
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Jerome I
JI
Amin
Najaf
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PP
Rudan
Igor
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Kraja
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Michael A
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Joel N
JN
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Cashell E
CE
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Christopher J
CJ
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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
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L Adrienne
LA
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Caroline S
CS
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Kari E
KE
D000368:Aged; D015992:Body Mass Index; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009765:Obesity / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D055105:Waist Circumference; D044465:White People / Q000235:genetics
D009419:Nerve Tissue Proteins; C082354:neurexin IIIalpha