Genome-wide association analysis identifies three new susceptibility loci for childhood body mass index

被引：254

作者：

Felix, Janine F. ^{[1
,2
,3
]}

Bradfield, Jonathan P. ^{[5
]}

Monnereau, Claire ^{[1
,2
,3
]}

van der Valk, Ralf J. P. ^{[9
]}

Stergiakouli, Evie ^{[12
]}

Chesi, Alessandra ^{[6
]}

Gaillard, Romy ^{[1
,2
,3
]}

Feenstra, Bjarke ^{[14
]}

Thiering, Elisabeth ^{[15
,16
]}

Kreiner-Moller, Eskil ^{[44
]}

Mahajan, Anubha ^{[18
]}

Pitkanen, Niina ^{[20
,24
]}

Joro, Raimo ^{[25
]}

Cavadino, Alana ^{[26
,27
]}

Huikari, Ville ^{[29
]}

Franks, Steve ^{[32
]}

Groen-Blokhuis, Maria M. ^{[34
]}

Cousminer, Diana L. ^{[35
]}

Marsh, Julie A. ^{[36
]}

Lehtimaki, Terho ^{[37
,38
]}

Curtin, John A. ^{[40
,41
]}

Vioque, Jesus ^{[42
,43
]}

Ahluwalia, Tarunveer S. ^{[44
,45
,46
]}

Myhre, Ronny ^{[47
]}

Price, Thomas S. ^{[49
]}

Vilor-Tejedor, Natalia ^{[43
,50
,51
]}

Yengo, Loic ^{[52
,53
]}

Grarup, Niels ^{[45
]}

Ntalla, Ioanna ^{[54
,55
]}

Ang, Wei ^{[36
]}

Atalay, Mustafa ^{[25
]}

Bisgaard, Hans ^{[44
]}

Blakemore, Alexandra I. ^{[33
]}

Bonnefond, Amelie ^{[52
,53
]}

Carstensen, Lisbeth ^{[14
]}

Eriksson, Johan ^{[56
]}

Flexeder, Claudia ^{[15
]}

Franke, Lude ^{[10
]}

Geller, Frank ^{[14
]}

Geserick, Mandy ^{[57
,58
]}

Hartikainen, Anna-Liisa ^{[30
]}

Haworth, Claire M. A. ^{[60
]}

Hirschhorn, Joel N. ^{[61
,62
,63
,64
]}

Hofman, Albert ^{[1
,3
]}

Holm, Jens-Christian ^{[65
,66
]}

Horikoshi, Momoko ^{[18
,19
]}

Hottenga, Jouke Jan ^{[34
]}

Huang, Jinyan ^{[67
]}

Kadarmideen, Haja N. ^{[68
]}

Kahonen, Mika ^{[39
,69
]}

机构：

[1] Univ Med Ctr Rotterdam, Erasmus MC, Generat Study Grp R, Rotterdam, Netherlands

[2] Univ Med Ctr Rotterdam, Erasmus MC, Dept Pediat, Rotterdam, Netherlands

[3] Univ Med Ctr Rotterdam, Erasmus MC, Dept Epidemiol, Room Na 2906,POB 2040, NL-3000 CA Rotterdam, Netherlands

[4] Univ Med Ctr Rotterdam, Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[5] Childrens Hosp Philadelphia, Ctr Appl Genom, Philadelphia, PA 19104 USA

[6] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA

[7] Childrens Hosp Philadelphia, Div Endocrinol, Philadelphia, PA 19104 USA

[8] Childrens Hosp Philadelphia, Div Gastroenterol Hepatol & Nutr, Philadelphia, PA 19104 USA

[9] Univ Groningen, Univ Med Ctr Groningen, Dept Pulmonol, GRIAC Groningen Res Inst Asthma & COPD, Groningen, Netherlands

[10] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[11] Univ Groningen, Univ Med Ctr Groningen, Dept Pediat Pulmonol & Pediat Allergol, Beatrix Childrens Hosp,GRIAC Groningen Res Inst A, Groningen, Netherlands

[12] Univ Bristol, MRC Integrat Epidemiol Unit, Bristol, Avon, England

[13] Univ Bristol, Sch Social & Community Med, ALSPAC, Bristol, Avon, England

[14] Statens Serum Inst, Dept Epidemiol Res, DK-2300 Copenhagen, Denmark

[15] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Epidemiol 1, Neuherberg, Germany

[16] Univ Munich, Med Ctr, Dr von Hauner Childrens Hosp, Div Metab & Nutr Med, Munich, Germany

[17] Naestved Hosp, Dept Pediat, Naestved, Denmark

[18] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[19] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England

[20] Univ Turku, Res Ctr Appl & Prevent Cardiovasc Med, Turku, Finland

[21] Univ Turku, Paavo Nurmi Ctr, Dept Hlth & Phys Act, Sports & Exercise Med Unit, Turku, Finland

[22] Univ Turku, Dept Clin Physiol & Nucl Med, Turku, Finland

[23] Univ Turku, Turku Univ Hosp, Dept Pediat, Turku, Finland

[24] Univ Eastern Finland, Inst Clin Med, Neurol, Kuopio, Finland

[25] Univ Eastern Finland, Inst Biomed, Physiol, Kuopio, Finland

[26] Queen Mary Univ London, Barts & London Sch Med & Dent, Wolfson Inst Prevent Med, Ctr Environm & Prevent Med, London, England

[27] UCL, UCL Inst Child Hlth, Populat Policy & Practice, London WC1E 6BT, England

[28] UCL, Dept Epidemiol & Publ Hlth, London WC1E 6BT, England

[29] Univ Oulu, Ctr Life Course Epidemiol, Oulu, Finland

[30] Univ Oulu, Inst Clin Med Obstet & Gynecol, Oulu, Finland

[31] Univ Oulu, Bioctr Oulu, Oulu, Finland

[32] Univ London Imperial Coll Sci Technol & Med, Inst Reprod & Dev Biol, London, England

[33] Univ London Imperial Coll Sci Technol & Med, Div Diabet Endocrinol & Metab, Sect Invest Med, Fac Med, London, England

[34] Vrije Univ Amsterdam, EMGO Inst Hlth & Care Res, Dept Biol Psychol, NCA Neurosci Campus Amsterdam, Amsterdam, Netherlands

[35] Univ Helsinki, Inst Mol Med Finland FIMM, Helsinki, Finland

[36] Univ Western Australia, Sch Womens & Infants Hlth, Perth, WA 6009, Australia

[37] Fimlab Labs, Dept Clin Chem, Tampere, Finland

[38] Univ Tampere, Sch Med, Dept Clin Chem, FIN-33101 Tampere, Finland

[39] Univ Tampere, Sch Med, Dept Clin Physiol, FIN-33101 Tampere, Finland

[40] Univ Manchester, Inst Inflammat & Repair, Ctr Resp Med & Allergy, Manchester, Lancs, England

[41] Univ S Manchester Hosp, Manchester Acad Hlth Sci Ctr, Manchester M20 8LR, Lancs, England

[42] Univ Miguel Hernandez, Elche Alicante, Spain

[43] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain

[44] Univ Copenhagen, Herlev & Gentofte Hosp, Copenhagen Prospect Studies Asthma Childhood, COPSAC, Copenhagen, Denmark

[45] Univ Copenhagen, Fac Hlth & Med Sci, Sect Metab Genet, Novo Nordisk Fdn Ctr Basic Metab Res, Copenhagen, Denmark

[46] Steno Diabet Ctr, DK-2820 Gentofte, Denmark

[47] Norwegian Inst Publ Hlth, Div Epidemiol, Dept Genes & Envrionm, Oslo, Norway

[48] Norwegian Inst Publ Hlth, Div Epidemiol, Oslo, Norway

[49] Univ Penn, Perelman Sch Med, Dept Syst Pharmacol & Translat Therapeut, Philadelphia, PA 19104 USA

[50] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain

来源：

HUMAN MOLECULAR GENETICS | 2016年 / 25卷 / 02期

基金：

芬兰科学院; 英国医学研究理事会; 欧洲研究理事会; 欧盟第七框架计划; 英国惠康基金; 英国工程与自然科学研究理事会; 中国博士后科学基金; 中国国家自然科学基金; 英国生物技术与生命科学研究理事会; 新加坡国家研究基金会; 加拿大健康研究院; 澳大利亚国家健康与医学研究理事会;

关键词：

ENVIRONMENTAL-FACTORS; GENE; METAANALYSIS; OBESITY; EXPRESSION; WEIGHT; VARIANTS; INSIGHTS; DISEASE; RAB27B;

D O I：

10.1093/hmg/ddv472

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

A large number of genetic loci are associated with adult body mass index. However, the genetics of childhood body mass index are largely unknown. We performed a meta-analysis of genome-wide association studies of childhood body mass index, using sex-and age-adjusted standard deviation scores. We included 35 668 children from 20 studies in the discovery phase and 11 873 children from 13 studies in the replication phase. In total, 15 loci reached genome-wide significance (P-value < 5 x 10(-8)) in the joint discovery and replication analysis, of which 12 are previously identified loci in or close to ADCY3, GNPDA2, TMEM18, SEC16B, FAIM2, FTO, TFAP2B, TNNI3K, MC4R, GPR61, LMX1B and OLFM4 associated with adult body mass index or childhood obesity. We identified three novel loci: rs13253111 near ELP3, rs8092503 near RAB27B and rs13387838 near ADAM23. Per additional risk allele, body mass index increased 0.04 Standard Deviation Score (SDS) [Standard Error (SE) 0.007], 0.05 SDS (SE 0.008) and 0.14 SDS (SE 0.025), for rs13253111, rs8092503 and rs13387838, respectively. A genetic risk score combining all 15 SNPs showed that each additional average risk allele was associated with a 0.073 SDS (SE 0.011, P-value = 3.12 x 10(-10)) increase in childhood body mass index in a population of 1955 children. This risk score explained 2% of the variance in childhood body mass index. This study highlights the shared genetic background between childhood and adult body mass index and adds three novel loci. These loci likely represent age-related differences in strength of the associations with body mass index.

引用

页码：389 / 403

页数：15

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