Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci

被引：28

作者：

Fernandez-Rhodes, Lindsay ^{[1
]}

Gong, Jian ^{[2
]}

Haessler, Jeffrey ^{[2
]}

Franceschini, Nora ^{[1
]}

Graff, Mariaelisa ^{[1
]}

Nishimura, Katherine K. ^{[2
]}

Wang, Yujie ^{[1
]}

Highland, Heather M. ^{[1
]}

Yoneyama, Sachiko ^{[1
]}

Bush, William S. ^{[3
]}

Goodloe, Robert ^{[4
]}

Ritchie, Marylyn D. ^{[5
]}

Crawford, Dana ^{[3
]}

Gross, Myron ^{[6
]}

Fornage, Myriam ^{[7
]}

Buzkova, Petra ^{[8
]}

Tao, Ran ^{[9
]}

Isasi, Carmen ^{[10
]}

Aviles-Santa, Larissa ^{[11
]}

Daviglus, Martha ^{[12
]}

Mackey, Rachel H. ^{[13
]}

Houston, Denise ^{[14
]}

Gu, C. Charles ^{[15
]}

Ehret, Georg ^{[16
,17
]}

Nguyen, Khanh-Dung H. ^{[16
]}

Lewis, Cora E. ^{[18
]}

Leppert, Mark ^{[19
]}

Irvin, Marguerite R. ^{[20
]}

Lim, Unhee ^{[21
]}

Haiman, Christopher A. ^{[22
]}

Le Marchand, Loic ^{[21
]}

Schumacher, Fredrick ^{[22
]}

Wilkens, Lynne ^{[21
]}

Lu, Yingchang ^{[23
]}

Bottinger, Erwin P. ^{[23
]}

Loos, Ruth J. L. ^{[23
]}

Sheu, Wayne H. -H. ^{[24
,25
]}

Guo, Xiuqing ^{[26
]}

Lee, Wen-Jane ^{[27
]}

Hai, Yang ^{[26
]}

Hung, Yi-Jen ^{[28
]}

Absher, Devin ^{[29
]}

Wu, I-Chien ^{[30
]}

Taylor, Kent D. ^{[26
]}

Lee, I-Te ^{[24
,25
]}

Liu, Yeheng ^{[26
]}

Wang, Tzung-Dau ^{[31
]}

Quertermous, Thomas ^{[32
]}

Juang, Jyh-Ming J. ^{[31
]}

Rotter, Jerome I. ^{[26
]}

机构：

[1] Univ North Carolina Chapel Hill, UNC Gillings Sch Global Publ Hlth, Dept Epidemiol, Chapel Hill, NC 27599 USA

[2] Fred Hutchinson Canc Res Ctr, Div Publ Hlth Sci, 1124 Columbia St, Seattle, WA 98104 USA

[3] Case Western Reserve Univ, Inst Computat Biol, Dept Epidemiol & Biostat, Cleveland, OH 44106 USA

[4] Vanderbilt Univ, Ctr Human Genet Res, 221 Kirkland Hall, Nashville, TN 37235 USA

[5] Penn State Univ, Biochem & Mol Biol, University Pk, PA 16802 USA

[6] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

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

[8] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA

[9] Univ North Carolina Chapel Hill, UNC Gillings Sch Global Publ Hlth, Dept Biostat, Chapel Hill, NC USA

[10] Albert Einstein Coll Med, Dept Epidemiol & Populat Hlth, Bronx, NY 10467 USA

[11] Natl Heart Lung & Blood Inst, Bethesda, MA USA

[12] Univ Illinois, Insitute Minor Hlth Res, Chicago, IL USA

[13] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Epidemiol, Pittsburgh, PA 15260 USA

[14] Wake Forest Sch Med, Geriatr & Gerontol, Winston Salem, NC USA

[15] Washington Univ, Sch Med, Div Biostat, St Louis, MO 63110 USA

[16] Johns Hopkins Univ, McKusick Nathans Inst Genet Med, Ctr Complex Dis Gen, Baltimore, MD USA

[17] Univ Hosp Geneva, Div Cardiol, Geneva, OH, Switzerland

[18] Univ Alabama Birmingham, Dept Med, Birmingham, AL 35294 USA

[19] Univ Utah, Dept Human Genet, Salt Lake City, UT 84112 USA

[20] Univ Alabama Birmingham, Dept Biostat, Birmingham, AL 35294 USA

[21] Univ Hawaii, Canc Ctr, Epidemiol Program, Honolulu, HI 96822 USA

[22] Univ Southern Calif, Keck Sch Med, Norris Comprehens Canc Ctr, Dept Prevent Med, Los Angeles, CA USA

[23] Icahn Sch Med Mt Sinai, Charles R Bronfman Inst Personalized Med, New York, NY 10029 USA

[24] Taichung Vet Gen Hosp, Dept Internal Med, Div Endocrine & Metab, Taichung, Taiwan

[25] Natl Yang Ming Univ, Natl Def Med Ctr, Sch Med, Taipei, Taiwan

[26] LABioMed Harbor UCLA Med Ctr, Inst Translat Genom & Populat Sci, Dept Pediat, Torrance, CA USA

[27] Taichung Vet Gen Hosp, Dept Med Res, Taichung, Taiwan

[28] Natl Def Med Ctr, Tri Serv Gen Hosp, Div Endocrinol & Metab, Taipei, Taiwan

[29] HudsonAlpha Inst Biotechnol, Huntsville, AL USA

[30] Natl Hlth Res Inst, Inst Populat Hlth Sci, Div Biostat & Bioinformat, Zhunan Town, Taiwan

[31] Natl Taiwan Univ Hosp, Cardiovasc Ctr, Dept Internal Med, Div Cardiol, Taipei, Taiwan

[32] Stanford Univ, Sch Med, Dept Med, Stanford, CA 94305 USA

来源：

HUMAN GENETICS | 2017年 / 136卷 / 06期

基金：

美国国家卫生研究院;

关键词：

WIDE ASSOCIATION; COMMON VARIANTS; METAANALYSIS; INDIVIDUALS; ADIPOSITY; TRAITS; US; PREVALENCE; AMERICANS; INSIGHTS;

D O I：

10.1007/s00439-017-1787-6

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of > 102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.

引用

页码：771 / 800

页数：30

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