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

Research output: Contribution to journalArticle

195 Citations (Scopus)

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 = 6.4×10 -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 (US)
Article numbere1000539
JournalPLoS Genetics
Volume5
Issue number6
DOIs
StatePublished - Jun 2009

Fingerprint

obesity
Genome-Wide Association Study
waist circumference
Waist Circumference
allele
genome
Abdominal Fat
body mass
loci
lending behavior
fat
nervous system disorder
Obesity
Alleles
abdominal fat
alleles
body mass index
Body Mass Index
diabetes
gene

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Heard-Costa, N. L., Carola Zillikens, M., Monda, K. L., Johansson, Å., Harris, T. B., Fu, M., ... North, K. E. (2009). NRXN3Is a novel locus for waist circumference: A genome-wide association study from the CHARGE consortium. PLoS Genetics, 5(6), [e1000539]. https://doi.org/10.1371/journal.pgen.1000539

NRXN3Is a novel locus for waist circumference : A genome-wide association study from the CHARGE consortium. / Heard-Costa, Nancy L.; Carola Zillikens, M.; Monda, Keri L.; Johansson, Åsa; 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.

In: PLoS Genetics, Vol. 5, No. 6, e1000539, 06.2009.

Research output: Contribution to journalArticle

Heard-Costa, NL, Carola Zillikens, M, Monda, KL, Johansson, Å, 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, YDI, 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, Cupples, LA, Fox, CS & North, KE 2009, 'NRXN3Is a novel locus for waist circumference: A genome-wide association study from the CHARGE consortium', PLoS Genetics, vol. 5, no. 6, e1000539. https://doi.org/10.1371/journal.pgen.1000539
Heard-Costa NL, Carola Zillikens M, Monda KL, Johansson Å, Harris TB, Fu M et al. NRXN3Is a novel locus for waist circumference: A genome-wide association study from the CHARGE consortium. PLoS Genetics. 2009 Jun;5(6). e1000539. https://doi.org/10.1371/journal.pgen.1000539
Heard-Costa, Nancy L. ; Carola Zillikens, M. ; Monda, Keri L. ; Johansson, Åsa ; 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. / NRXN3Is a novel locus for waist circumference : A genome-wide association study from the CHARGE consortium. In: PLoS Genetics. 2009 ; Vol. 5, No. 6.
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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 = 6.4×10 -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.",
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T1 - NRXN3Is a novel locus for waist circumference

T2 - A genome-wide association study from the CHARGE consortium

AU - Heard-Costa, Nancy L.

AU - Carola Zillikens, M.

AU - Monda, Keri L.

AU - Johansson, Åsa

AU - Harris, Tamara B.

AU - Fu, Mao

AU - Haritunians, Talin

AU - Feitosa, Mary F.

AU - Aspelund, Thor

AU - Eiriksdottir, Gudny

AU - Garcia, Melissa

AU - Launer, Lenore J.

AU - Smith, Albert V.

AU - Mitchell, Braxton D.

AU - McArdle, Patrick F.

AU - Shuldiner, Alan R.

AU - Bielinski, Suzette J.

AU - Boerwinkle, Eric

AU - Brancati, Fred

AU - Demerath, Ellen W.

AU - Pankow, James S.

AU - Arnold, Alice M.

AU - Chen, Yii Der Ida

AU - Glazer, Nicole L.

AU - McKnight, Barbara

AU - Psaty, Bruce M.

AU - Rotter, Jerome I.

AU - Amin, Najaf

AU - Campbell, Harry

AU - Gyllensten, Ulf

AU - Pattaro, Cristian

AU - Pramstaller, Peter P.

AU - Rudan, Igor

AU - Struchalin, Maksim

AU - Vitart, Veronique

AU - Gao, Xiaoyi

AU - Kraja, Aldi

AU - Province, Michael A.

AU - Zhang, Qunyuan

AU - Atwood, Larry D.

AU - Dupuis, Josée

AU - Hirschhorn, Joel N.

AU - Jaquish, Cashell E.

AU - O'Donnell, Christopher J.

AU - Vasan, Ramachandran S.

AU - White, Charles C.

AU - Aulchenko, Yurii S.

AU - Estrada, Karol

AU - Hofman, Albert

AU - Rivadeneira, Fernando

AU - Uitterlinden, André G.

AU - Witteman, Jacqueline C M

AU - Oostra, Ben A.

AU - Kaplan, Robert C.

AU - Gudnason, Vilmundur

AU - O'Connell, Jeffrey R.

AU - Borecki, Ingrid B.

AU - Van Duijn, Cornelia M.

AU - Cupples, L. Adrienne

AU - Fox, Caroline S.

AU - North, Kari E.

PY - 2009/6

Y1 - 2009/6

N2 - 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.

AB - 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.

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