Discovery and fine-mapping of adiposity loci using high density imputation of genome-wide association studies in individuals of African ancestry: African Ancestry Anthropometry Genetics Consortium

被引：74

作者：

Ng, Maggie C. Y. ^{[1
,2
]}

Graff, Mariaelisa ^{[3
]}

Lu, Yingchang ^{[4
]}

Justice, Anne E. ^{[3
]}

Mudgal, Poorva ^{[2
]}

Liu, Ching-Ti ^{[5
]}

Young, Kristin ^{[3
]}

Yanek, Lisa R. ^{[6
]}

Feitosa, Mary F. ^{[7
]}

Wojczynski, Mary K. ^{[7
]}

Rand, Kristin ^{[8
]}

Brody, Jennifer A. ^{[9
]}

Cade, Brian E. ^{[10
,11
]}

Dimitrov, Latchezar ^{[1
]}

Duan, Qing ^{[12
]}

Guo, Xiuqing ^{[13
]}

Lange, Leslie A. ^{[12
]}

Nalls, Michael A. ^{[14
,15
]}

Okut, Hayrettin ^{[2
]}

Tajuddin, Salman M. ^{[16
]}

Tayo, Bamidele O. ^{[17
]}

Vedantam, Sailaja ^{[18
,19
,20
]}

Bradfield, Jonathan P. ^{[21
]}

Chen, Guanjie ^{[22
]}

Chen, Wei-Min ^{[23
,24
]}

Chesi, Alessandra ^{[25
]}

Irvin, Marguerite R. ^{[26
]}

Padhukasahasram, Badri ^{[27
]}

Smith, Jennifer A. ^{[28
]}

Zheng, Wei ^{[29
]}

Allison, Matthew A. ^{[30
]}

Ambrosone, Christine B. ^{[31
]}

Bandera, Elisa V. ^{[32
]}

Bartz, Traci M. ^{[33
,34
]}

Berndt, Sonja I. ^{[35
]}

Bernstein, Leslie ^{[36
]}

Blot, William J. ^{[37
]}

Bottinger, Erwin P. ^{[4
]}

Carpten, John ^{[38
]}

Chanock, Stephen J.

Chen, Yii-Der Ida ^{[13
]}

Conti, David V. ^{[8
]}

Cooper, Richard S. ^{[17
]}

Fornage, Myriam ^{[39
]}

Freedman, Barry I. ^{[40
]}

Garcia, Melissa ^{[16
]}

Goodman, Phyllis J. ^{[41
]}

Hsu, Yu-Han H. ^{[18
,19
,20
,42
]}

Hu, Jennifer ^{[43
,44
]}

Huff, Chad D. ^{[45
]}

机构：

[1] Wake Forest Sch Med, Ctr Genom & Personalized Med Res, Salem, NC USA

[2] Wake Forest Sch Med, Ctr Diabet Res, Winston Salem, NC USA

[3] Univ N Carolina, Dept Epidemiol, Chapel Hill, NC USA

[4] Icachn Sch Med Mt Sinai, Charles Bronfman Inst Personalized Med, New York, NY USA

[5] Boston Univ, Sch Publ Hlth, Dept Biostat, Boston, MA USA

[6] Johns Hopkins Univ, Sch Med, Dept Med, Baltimore, MD 21205 USA

[7] Washington Univ, Sch Med, Dept Genet, Div Stat Genom, St Louis, MO 63110 USA

[8] Univ Southern Calif, Dept Prevent Med, Keck Sch Med, Los Angeles, CA 90089 USA

[9] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[10] Brigham & Womens Hosp, Div Sleep & Circadian Disorders, 75 Francis St, Boston, MA 02115 USA

[11] Harvard Med Sch, Boston, MA USA

[12] Univ North Carolina Chapel Hill, Dept Genet, Chapel Hill, NC USA

[13] Harbor UCLA Med Ctr, Los Angeles Biomed Res Inst, Inst Translat Genom & Populat Sci, Torrance, CA 90509 USA

[14] NIA, Lab Neurogenet, NIH, Bethesda, MD 20892 USA

[15] Data Tecn Int, Glen Echo, MD USA

[16] NIA, NIH, Baltimore, MD 21224 USA

[17] Loyola Univ Chicago, Stritch Sch Med, Dept Publ Hlth Sci, Maywood, IL USA

[18] Boston Childrens Hosp, Div Endocrinol, Boston, MA USA

[19] Boston Childrens Hosp, Ctr Basic & Translat Obes Res, Boston, MA USA

[20] Broad Inst MIT & Harvard, Cambridge, MA USA

[21] Childrens Hosp Philadelphia, Ctr Appl Gen, Philadelphia, PA 19104 USA

[22] NHGRI, Ctr Res Genom & Global Hlth, NIH, Bethesda, MD 20892 USA

[23] Univ Virginia, Sch Med, Dept Publ Hlth Sci, Charlottesville, VA 22908 USA

[24] Univ Virginia, Sch Med, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA

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

[26] Univ Alabama Birmingham, Dept Epidemiol, Birmingham, AL USA

[27] Henry Ford Hlth Syst, Ctr Hlth Policy & Hlth Serv Res, Detroit, MI USA

[28] Univ Michigan, Dept Epidemiol, Ann Arbor, MI 48109 USA

[29] Vanderbilt Univ, Sch Med, Vanderbilt Epidemiol Ctr, Div Epidemiol,Dept Med, Nashville, TN 37212 USA

[30] Univ Calif San Diego, Div Prevent Med, Dept Family Med & Publ Hlth, La Jolla, CA 92093 USA

[31] Roswell Pk Canc Inst, Dept Canc Prevent & Control, Buffalo, NY 14263 USA

[32] Rutgers Canc Inst New Jersey, Dept Populat Sci, New Brunswick, NJ USA

[33] Univ Washington, Dept Med, Cardiovasc Hlth Res Unit, Seattle, WA USA

[34] Univ Washington, Dept Biostat, Cardiovasc Hlth Res Unit, Seattle, WA 98195 USA

[35] NCI, Div Canc Epidemiol & Genet, Rockville, MD USA

[36] City Hope Natl Med Ctr, Beckman Res Inst, Duarte, CA USA

[37] Int Epidemiol Inst, Rockville, MD USA

[38] Univ Southern Calif, Keck Sch Med, Dept Translat Genom, Los Angeles, CA 90033 USA

[39] Univ Texas Hlth Sci Ctr Houston, Ctr Human Genet, Houston, TX 77030 USA

[40] Wake Forest Sch Med, Dept Internal Med, Winston Salem, NC USA

[41] Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA

[42] Harvard Med Sch, Program Bioinformat & Integrat Genom, Boston, MA USA

[43] Univ Miami, Sylvester Comprehens Canc Ctr, Leonard Miller Sch Med, Miami, FL USA

[44] Univ Miami, Dept Publ Hlth Sci, Leonard Miller Sch Med, Miami, FL USA

[45] Univ Texas MD Anderson Canc Ctr, Dept Epidemiol, Houston, TX 77030 USA

[46] Univ Southern Calif, Norris Comprehens Canc Ctr, Los Angeles, CA 90007 USA

[47] Canc Prevent Inst Calif, Fremont, CA USA

[48] Stanford Univ, Sch Med, Dept Hlth Res & Policy Epidemiol, Stanford, CA USA

[49] Stanford Univ, Sch Med, Stanford Canc Inst, Stanford, CA USA

[50] Univ Arizona, Dept Surg, Div Urol, Tucson, AZ USA

来源：

PLOS GENETICS | 2017年 / 13卷 / 04期

基金：

美国国家卫生研究院;

关键词：

BODY-MASS INDEX; COMMON VARIANTS; METAANALYSIS; OBESITY; ARCHITECTURE; CANCER; DIFFERENTIATION; ANNOTATION; RESISTANCE; AUTOTAXIN;

D O I：

10.1371/journal.pgen.1006719

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies (GWAS) have identified >300 loci associated with measures of adiposity including body mass index (BMI) and waist-to-hip ratio (adjusted for BMI, WHRadjBMI), but few have been identified through screening of the African ancestry genomes. We performed large scale meta-analyses and replications in up to 52,895 individuals for BMI and up to 23,095 individuals for WHRadjBMI from the African Ancestry Anthropometry Genetics Consortium (AAAGC) using 1000 Genomes phase 1 imputed GWAS to improve coverage of both common and low frequency variants in the low linkage disequilibrium African ancestry genomes. In the sex-combined analyses, we identified one novel locus (TCF7L2/HABP2) for WHRadjBMI and eight previously established loci at P < 5x10(-8) : seven for BMI, and one for WHRadjBMI in African ancestry individuals. An additional novel locus (SPRYD7/DLEU2) was identified for WHRadjBMI when combined with European GWAS. In the sex-stratified analyses, we identified three novel loci for BMI (INTS10/LPL and MLC1 in men, IRX4/IRX2 in women) and four for WHRadjBMI (SSX2IP, CASC8, PDE3B and ZDHHC1/HSD11B2 in women) in individuals of African ancestry or both African and European ancestry. For four of the novel variants, the minor allele frequency was low (<5%). In the trans-ethnic fine mapping of 47 BMI loci and 27 WHRadjBMI loci that were locus-wide significant (P < 0.05 adjusted for effective number of variants per locus) from the African ancestry sex-combined and sex-stratified analyses, 26 BMI loci and 17 WHRadjBMI loci contained <= 20 variants in the credible sets that jointly account for 99% posterior probability of driving the associations. The lead variants in 13 of these loci had a high probability of being causal. As compared to our previous HapMap imputed GWAS for BMI and WHRadjBMI including up to 71,412 and 27,350 African ancestry individuals, respectively, our results suggest that 1000 Genomes imputation showed modest improvement in identifying GWAS loci including low frequency variants. Trans-ethnic meta-analyses further improved fine mapping of putative causal variants in loci shared between the African and European ancestry populations.

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页数：25

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