Contribution of common non-synonymous variants in PCSK1 to body-mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331,175 individuals

Kevin T Nead; Aihua Li; Mackenzie R Wehner; Binod Neupane; Stefan Gustafsson; Adam Butterworth; James C Engert; A Darlene Davis; Robert A Hegele; Ruby Miller; Marcel den Hoed; Kay-Tee Khaw; Tuomas Oskari Kilpeläinen; Nick Wareham; Todd L Edwards; Göran Hallmans; Tibor V Varga; Sharon L R Kardia; Jennifer A Smith; Wei Zhao; Jessica D Faul; David Weir; Jie Mi; Bo Xi; Samuel Canizales Quinteros; Cyrus Cooper; Avan Aihie Sayer; Karen Jameson; Anders Grøntved; Myriam Fornage; Stephen Sidney; Craig L Hanis; Heather M Highland; Hans-Ulrich Häring; Martin Heni; Jessica Lasky-Su; Scott T Weiss; Glenn S Gerhard; Christopher Still; Melkaey M Melka; Zdenka Pausova; Tomáš Paus; Struan F A Grant; Hakon Hakonarson; R Arlen Price; Kai Wang; Andre Scherag; Johannes Hebebrand; Anke Hinney; Paul W Franks; BioBank Japan

doi:10.1093/hmg/ddv097

Contribution of common non-synonymous variants in PCSK1 to body-mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331,175 individuals

Kevin T Nead, Aihua Li, Mackenzie R Wehner, Binod Neupane, Stefan Gustafsson, Adam Butterworth, James C Engert, A Darlene Davis, Robert A Hegele, Ruby Miller, Marcel den Hoed, Kay-Tee Khaw, Tuomas Oskari Kilpeläinen, Nick Wareham, Todd L Edwards, Göran Hallmans, Tibor V Varga, Sharon L R Kardia, Jennifer A Smith, Wei ZhaoJessica D Faul, David Weir, Jie Mi, Bo Xi, Samuel Canizales Quinteros, Cyrus Cooper, Avan Aihie Sayer, Karen Jameson, Anders Grøntved, Myriam Fornage, Stephen Sidney, Craig L Hanis, Heather M Highland, Hans-Ulrich Häring, Martin Heni, Jessica Lasky-Su, Scott T Weiss, Glenn S Gerhard, Christopher Still, Melkaey M Melka, Zdenka Pausova, Tomáš Paus, Struan F A Grant, Hakon Hakonarson, R Arlen Price, Kai Wang, Andre Scherag, Johannes Hebebrand, Anke Hinney, Paul W Franks, BioBank Japan

29 Citations (Scopus)

Abstract

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m²], but their contribution to common obesity (BMI ≥ 30 kg/m²) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10^-6) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10^-7). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10^-4). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

Original language	English
Journal	Human Molecular Genetics
Volume	24
Issue number	2
Pages (from-to)	3582–3594
Number of pages	13
ISSN	0964-6906
DOIs	https://doi.org/10.1093/hmg/ddv097
Publication status	Published - 18 Jan 2015

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Nead, K. T., Li, A., Wehner, M. R., Neupane, B., Gustafsson, S., Butterworth, A., Engert, J. C., Davis, A. D., Hegele, R. A., Miller, R., den Hoed, M., Khaw, K.-T., Oskari Kilpeläinen, T., Wareham, N., Edwards, T. L., Hallmans, G., Varga, T. V., Kardia, S. L. R., Smith, J. A., ... BioBank Japan (2015). Contribution of common non-synonymous variants in PCSK1 to body-mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331,175 individuals. Human Molecular Genetics, 24(2), 3582–3594. https://doi.org/10.1093/hmg/ddv097

Contribution of common non-synonymous variants in PCSK1 to body-mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331,175 individuals. / Nead, Kevin T; Li, Aihua; Wehner, Mackenzie R et al.
In: Human Molecular Genetics, Vol. 24, No. 2, 18.01.2015, p. 3582–3594.

Research output: Contribution to journal › Journal article › Research › peer-review

Nead, KT, Li, A, Wehner, MR, Neupane, B, Gustafsson, S, Butterworth, A, Engert, JC, Davis, AD, Hegele, RA, Miller, R, den Hoed, M, Khaw, K-T, Oskari Kilpeläinen, T, Wareham, N, Edwards, TL, Hallmans, G, Varga, TV, Kardia, SLR, Smith, JA, Zhao, W, Faul, JD, Weir, D, Mi, J, Xi, B, Canizales Quinteros, S, Cooper, C, Sayer, AA, Jameson, K, Grøntved, A, Fornage, M, Sidney, S, Hanis, CL, Highland, HM, Häring, H-U, Heni, M, Lasky-Su, J, Weiss, ST, Gerhard, GS, Still, C, Melka, MM, Pausova, Z, Paus, T, Grant, SFA, Hakonarson, H, Price, RA, Wang, K, Scherag, A, Hebebrand, J, Hinney, A, Franks, PW & BioBank Japan 2015, 'Contribution of common non-synonymous variants in PCSK1 to body-mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331,175 individuals', Human Molecular Genetics, vol. 24, no. 2, pp. 3582–3594. https://doi.org/10.1093/hmg/ddv097

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title = "Contribution of common non-synonymous variants in PCSK1 to body-mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331,175 individuals",

abstract = "Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m2], but their contribution to common obesity (BMI ≥ 30 kg/m2) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10-6) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10-7). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10-4). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.",

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T1 - Contribution of common non-synonymous variants in PCSK1 to body-mass index variation and risk of obesity

T2 - a systematic review and meta-analysis with evidence from up to 331,175 individuals

AU - Nead, Kevin T

AU - Li, Aihua

AU - Wehner, Mackenzie R

AU - Neupane, Binod

AU - Gustafsson, Stefan

AU - Butterworth, Adam

AU - Engert, James C

AU - Davis, A Darlene

AU - Hegele, Robert A

AU - Miller, Ruby

AU - den Hoed, Marcel

AU - Khaw, Kay-Tee

AU - Oskari Kilpeläinen, Tuomas

AU - Wareham, Nick

AU - Edwards, Todd L

AU - Hallmans, Göran

AU - Varga, Tibor V

AU - Kardia, Sharon L R

AU - Smith, Jennifer A

AU - Zhao, Wei

AU - Faul, Jessica D

AU - Weir, David

AU - Mi, Jie

AU - Xi, Bo

AU - Canizales Quinteros, Samuel

AU - Cooper, Cyrus

AU - Sayer, Avan Aihie

AU - Jameson, Karen

AU - Grøntved, Anders

AU - Fornage, Myriam

AU - Sidney, Stephen

AU - Hanis, Craig L

AU - Highland, Heather M

AU - Häring, Hans-Ulrich

AU - Heni, Martin

AU - Lasky-Su, Jessica

AU - Weiss, Scott T

AU - Gerhard, Glenn S

AU - Still, Christopher

AU - Melka, Melkaey M

AU - Pausova, Zdenka

AU - Paus, Tomáš

AU - Grant, Struan F A

AU - Hakonarson, Hakon

AU - Price, R Arlen

AU - Wang, Kai

AU - Scherag, Andre

AU - Hebebrand, Johannes

AU - Hinney, Anke

AU - Franks, Paul W

AU - BioBank Japan

PY - 2015/1/18

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N2 - Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m2], but their contribution to common obesity (BMI ≥ 30 kg/m2) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10-6) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10-7). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10-4). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

AB - Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m2], but their contribution to common obesity (BMI ≥ 30 kg/m2) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331 175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CIs) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR = 1.15, 95% CI 1.06-1.24, P = 6.08 × 10-6) and rs6234/rs6235 (OR = 1.07, 95% CI 1.04-1.10, P = 3.00 × 10-7). Similarly, significant associations were found with continuous BMI for rs6232 (β = 0.03, 95% CI 0.00-0.07; P = 0.047) and rs6234/rs6235 (β = 0.02, 95% CI 0.00-0.03; P = 5.57 × 10-4). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology.

U2 - 10.1093/hmg/ddv097

DO - 10.1093/hmg/ddv097

M3 - Journal article

C2 - 25784503

SN - 0964-6906

VL - 24

SP - 3582

EP - 3594

JO - Human Molecular Genetics

JF - Human Molecular Genetics

IS - 2

ER -

Contribution of common non-synonymous variants in PCSK1 to body-mass index variation and risk of obesity: a systematic review and meta-analysis with evidence from up to 331,175 individuals

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