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 O Kilpeläinen, Nick Wareham, Todd L Edwards, Göran Hallmans, Tibor V Varga, Sharon L R Kardia, Jennifer A Smith, Wei Zhao & 31 andre 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, AGEN-BMI, GIANT Consortium

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) 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.

OriginalsprogEngelsk
TidsskriftHuman Molecular Genetics
Vol/bind24
Udgave nummer12
Sider (fra-til)3582-94
Antal sider13
ISSN0964-6906
DOI
StatusUdgivet - 2015

Fingeraftryk

Meta-Analysis
Body Mass Index
Confidence Intervals
Genome-Wide Association Study
Odds Ratio
PubMed

Citer dette

Nead, Kevin T ; Li, Aihua ; Wehner, Mackenzie R ; Neupane, Binod ; Gustafsson, Stefan ; Butterworth, Adam ; Engert, James C ; Davis, A Darlene ; Hegele, Robert A ; Miller, Ruby ; den Hoed, Marcel ; Khaw, Kay-Tee ; Kilpeläinen, Tuomas O ; Wareham, Nick ; Edwards, Todd L ; Hallmans, Göran ; Varga, Tibor V ; Kardia, Sharon L R ; Smith, Jennifer A ; Zhao, Wei ; Faul, Jessica D ; Weir, David ; Mi, Jie ; Xi, Bo ; Quinteros, Samuel Canizales ; Cooper, Cyrus ; Sayer, Avan Aihie ; Jameson, Karen ; Grøntved, Anders ; Fornage, Myriam ; Sidney, Stephen ; Hanis, Craig L ; Highland, Heather M ; Häring, Hans-Ulrich ; Heni, Martin ; Lasky-Su, Jessica ; Weiss, Scott T ; Gerhard, Glenn S ; Still, Christopher ; Melka, Melkaey M ; Pausova, Zdenka ; Paus, Tomáš ; Grant, Struan F A ; Hakonarson, Hakon ; Price, R Arlen ; Wang, Kai ; Scherag, Andre ; Hebebrand, Johannes ; Hinney, Anke ; Franks, Paul W ; BioBank Japan, AGEN-BMI, GIANT Consortium. / 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. I: Human Molecular Genetics. 2015 ; Bind 24 , Nr. 12. s. 3582-94.
@article{0050d48a56f94bbbbe0e597281028348,
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/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) 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.",
author = "Nead, {Kevin T} and Aihua Li and Wehner, {Mackenzie R} and Binod Neupane and Stefan Gustafsson and Adam Butterworth and Engert, {James C} and Davis, {A Darlene} and Hegele, {Robert A} and Ruby Miller and {den Hoed}, Marcel and Kay-Tee Khaw and Kilpel{\"a}inen, {Tuomas O} and Nick Wareham and Edwards, {Todd L} and G{\"o}ran Hallmans and Varga, {Tibor V} and Kardia, {Sharon L R} and Smith, {Jennifer A} and Wei Zhao and Faul, {Jessica D} and David Weir and Jie Mi and Bo Xi and Quinteros, {Samuel Canizales} and Cyrus Cooper and Sayer, {Avan Aihie} and Karen Jameson and Anders Gr{\o}ntved and Myriam Fornage and Stephen Sidney and Hanis, {Craig L} and Highland, {Heather M} and Hans-Ulrich H{\"a}ring and Martin Heni and Jessica Lasky-Su and Weiss, {Scott T} and Gerhard, {Glenn S} and Christopher Still and Melka, {Melkaey M} and Zdenka Pausova and Tom{\'a}š Paus and Grant, {Struan F A} and Hakon Hakonarson and Price, {R Arlen} and Kai Wang and Andre Scherag and Johannes Hebebrand and Anke Hinney and Franks, {Paul W} and {BioBank Japan, AGEN-BMI, GIANT Consortium}",
note = "{\circledC} The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
year = "2015",
doi = "10.1093/hmg/ddv097",
language = "English",
volume = "24",
pages = "3582--94",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Heinemann",
number = "12",

}

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, Kilpeläinen, TO, Wareham, N, Edwards, TL, Hallmans, G, Varga, TV, Kardia, SLR, Smith, JA, Zhao, W, Faul, JD, Weir, D, Mi, J, Xi, B, Quinteros, SC, 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, AGEN-BMI, GIANT Consortium 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, bind 24 , nr. 12, s. 3582-94. 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; Neupane, Binod; Gustafsson, Stefan; Butterworth, Adam; Engert, James C; Davis, A Darlene; Hegele, Robert A; Miller, Ruby; den Hoed, Marcel; Khaw, Kay-Tee; Kilpeläinen, Tuomas O; Wareham, Nick; Edwards, Todd L; Hallmans, Göran; Varga, Tibor V; Kardia, Sharon L R; Smith, Jennifer A; Zhao, Wei; Faul, Jessica D; Weir, David; Mi, Jie; Xi, Bo; Quinteros, Samuel Canizales; Cooper, Cyrus; Sayer, Avan Aihie; Jameson, Karen; Grøntved, Anders; Fornage, Myriam; Sidney, Stephen; Hanis, Craig L; Highland, Heather M; Häring, Hans-Ulrich; Heni, Martin; Lasky-Su, Jessica; Weiss, Scott T; Gerhard, Glenn S; Still, Christopher; Melka, Melkaey M; Pausova, Zdenka; Paus, Tomáš; Grant, Struan F A; Hakonarson, Hakon; Price, R Arlen; Wang, Kai; Scherag, Andre; Hebebrand, Johannes; Hinney, Anke; Franks, Paul W; BioBank Japan, AGEN-BMI, GIANT Consortium.

I: Human Molecular Genetics, Bind 24 , Nr. 12, 2015, s. 3582-94.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

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 - Kilpeläinen, Tuomas O

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 - Quinteros, Samuel Canizales

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, AGEN-BMI, GIANT Consortium

N1 - © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2015

Y1 - 2015

N2 - Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity [e.g. body mass index (BMI) ≥ 40 kg/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) 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/m(2)], but their contribution to common obesity (BMI ≥ 30 kg/m(2)) 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

VL - 24

SP - 3582

EP - 3594

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 12

ER -