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.

TitleContribution 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.
Publication TypeJournal Article
Year of Publication2015
AuthorsNead, KT, Li, A, Wehner, MR, Neupane, B, Gustafsson, S, Butterworth, AS, Engert, JC, A Davis, D, 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, DR, Mi, J, Xi, B, Quinteros, SCanizales, Cooper, C, Sayer, AAihie, 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, R Price, A, Wang, K, Scherag, A, Hebebrand, J, Hinney, A, Franks, PW, Frayling, TM, McCarthy, MI, Hirschhorn, J, Loos, RJF, Ingelsson, E, Gerstein, HC, Yusuf, S, Beyene, J, Anand, SS, Meyre, D
Corporate AuthorsBioBank Japan, AGEN-BMI, GIANT Consortium
JournalHuman Molecular Genetics
Volume24
Issue12
Pagination3582-94
Date Published2015 Jun 15
ISSN Number1460-2083
KeywordsAlleles, BMI, Genetics, Meta-analyses, Obesity, Older Adults
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.

DOI10.1093/hmg/ddv097
Alternate JournalHum. Mol. Genet.
Citation Key8616
PubMed ID25784503
PubMed Central IDPMC4498155
Grant List14136 / / Cancer Research UK / United Kingdom
DK072488 / DK / NIDDK NIH HHS / United States
DK088231 / DK / NIDDK NIH HHS / United States
G1000143 / / Medical Research Council / United Kingdom
MC_U106179471 / / Medical Research Council / United Kingdom
MC_UP_A620_1014 / / Medical Research Council / United Kingdom
MC_UP_A620_1015 / / Medical Research Council / United Kingdom
MC_UU_12011/1 / / Medical Research Council / United Kingdom
MC_UU_12011/2 / / Medical Research Council / United Kingdom
MC_UU_12015/1 / / Medical Research Council / United Kingdom
MR/L003120/1 / / Medical Research Council / United Kingdom
P01 HL083069 / HL / NHLBI NIH HHS / United States
P30 DK072488 / DK / NIDDK NIH HHS / United States
RG/08/014/24067 / / British Heart Foundation / United Kingdom
T32 HL07427 / HL / NHLBI NIH HHS / United States
U01 HL076419 / HL / NHLBI NIH HHS / United States
U01 HL65899 / HL / NHLBI NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada