Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations

被引：66

作者：

Ge, Tian ^{[1
,2
,3
,4
]}

Irvin, Marguerite R. ^{[5
]}

Patki, Amit ^{[6
]}

Srinivasasainagendra, Vinodh ^{[6
]}

Lin, Yen-Feng ^{[7
,8
,9
]}

Tiwari, Hemant K. ^{[6
]}

Armstrong, Nicole D. ^{[5
]}

Benoit, Barbara ^{[10
]}

Chen, Chia-Yen ^{[11
]}

Choi, Karmel W. ^{[1
,2
,3
]}

Cimino, James J. ^{[12
]}

Davis, Brittney H. ^{[13
]}

Dikilitas, Ozan ^{[14
,15
]}

Etheridge, Bethany ^{[13
]}

Feng, Yen-Chen Anne ^{[1
,16
]}

Gainer, Vivian ^{[10
]}

Huang, Hailiang ^{[4
,17
,18
]}

Jarvik, Gail P. ^{[19
]}

Kachulis, Christopher ^{[4
]}

Kenny, Eimear E. ^{[20
]}

Khan, Atlas ^{[21
]}

Kiryluk, Krzysztof ^{[21
]}

Kottyan, Leah ^{[22
]}

Kullo, Iftikhar J. ^{[14
]}

Lange, Christoph ^{[23
]}

Lennon, Niall ^{[4
]}

Leong, Aaron ^{[4
,24
,25
]}

Malolepsza, Edyta ^{[4
]}

Miles, Ayme D. ^{[12
]}

Murphy, Shawn ^{[26
]}

Namjou, Bahram ^{[22
]}

Narayan, Renuka ^{[13
]}

O'Connor, Mark J. ^{[27
]}

Pacheco, Jennifer A. ^{[28
]}

Perez, Emma ^{[29
,30
]}

Rasmussen-Torvik, Laura J. ^{[31
]}

Rosenthal, Elisabeth A. ^{[19
]}

Schaid, Daniel ^{[32
]}

Stamou, Maria ^{[33
]}

Udler, Miriam S. ^{[1
,4
,17
]}

Wei, Wei-Qi ^{[34
]}

Weiss, Scott T. ^{[35
]}

Ng, Maggie C. Y. ^{[36
]}

Smoller, Jordan W. ^{[1
,2
,3
,4
]}

Lebo, Matthew S. ^{[4
,30
,37
]}

Meigs, James B. ^{[4
,17
,24
]}

Limdi, Nita A. ^{[13
]}

Karlson, Elizabeth W. ^{[29
,30
]}

机构：

[1] Massachusetts Gen Hosp, Ctr Gen Med, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Ctr Precis Psychiat, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Univ Alabama Birmingham, Sch Publ Hlth, Dept Epidmiol, Birmingham, AL 35294 USA

[6] Univ Alabama Birmingham, Sch Publ Hlth, Dept Biostat, Birmingham, AL 35294 USA

[7] Natl Hlth Res Inst, Ctr Neuropsychiat Res, Miaoli, Taiwan

[8] Natl Yang Ming Chiao Tung Univ, Sch Med, Dept Publ Hlth & Med Humanities, Taipei, Taiwan

[9] Natl Cheng Kung Univ, Inst Behav Med, Coll Med, Tainan, Taiwan

[10] Mass Gen Brigham Res Informat Sci & Comp, Boston, MA USA

[11] Biogen Inc, Translat Biol, Cambridge, MA USA

[12] Univ Alabama Birmingham, Informat Inst, Birmingham, AL USA

[13] Univ Alabama Birmingham, Sch Med, Dept Neurol, Birmingham, AL USA

[14] Mayo Clin, Dept Cardiovasc Med, Rochester, MN 55905 USA

[15] Mayo Clin, Dept Internal Med, Investigator Training Program, Rochester, MN 55905 USA

[16] Natl Taiwan Univ, Inst Epidmiol & Prevent Med, Taipei, Taiwan

[17] Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA

[18] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[19] Univ Washington, Dept Med, Div Med Genet, Seattle, WA USA

[20] Icahn Sch Med Mt Sinai, Inst Gen Hlth, New York, NY 10029 USA

[21] Columbia Univ, Vagelos Coll Phys & Surg, Dept Med, Div Nephrol, New York, NY USA

[22] Ctr Cincinnati Childrens Hosp Med Ctr, Ctr Autoimmune Genom & Etiol, Cincinnati, OH USA

[23] Harvard TH Chan Sch Publ Hlth, Dept Biostat, Boston, MA USA

[24] Massachusetts Gen Hosp, Div Gen Internal Med, Boston, MA 02114 USA

[25] Massachusetts Gen Hosp, Diabet Unit, Boston, MA 02114 USA

[26] Massachusetts Gen Hosp, Dept Neurol, Boston, MA 02114 USA

[27] UMass Mem Hlth Care, Worcester, MA USA

[28] Northwestern Univ, Ctr Genet Med, Feinberg Sch Med, Chicago, IL 60630 USA

[29] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[30] Mass Gen Brigham Personalized Med, Boston, MA USA

[31] Northwestern Univ, Feinberg Sch Med, Dept Prevent Med, Chicago, IL 60630 USA

[32] Mayo Clin, Dept Quantitat Hlth Sci, Rochester, MN 55905 USA

[33] Massachusetts Gen Hosp, Div Endocrinol, Boston, MA 02114 USA

[34] Vanderbilt Univ, Dept Biomed Informat, Med Ctr, 221 Kirkland Hall, Nashville, TN 37235 USA

[35] Brigham & Womens Hosp, Channing Div Network Med, Dept Med, Boston, MA USA

[36] Vanderbilt Univ Sch Med, Vanderbilt Genet Inst, Div Med Genet, Nashville, TN USA

[37] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

来源：

GENOME MEDICINE | 2022年 / 14卷 / 01期

关键词：

Polygenic risk score; Type; 2; diabetes; Diverse populations; Clinical implementation; GENETIC RISK; GENOME-WIDE; PREDICTION; DISEASE; TRIAL;

D O I：

10.1186/s13073-022-01074-2

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Background Type 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for equitable deployment of PRS to clinical practice that benefits global populations. Methods We integrated T2D GWAS in European, African, and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and assessed the prediction accuracy of the PRS in the multi-ethnic Electronic Medical Records and Genomics (eMERGE) study (11,945 cases; 57,694 controls), four Black cohorts (5137 cases; 9657 controls), and the Taiwan Biobank (4570 cases; 84,996 controls). We additionally evaluated a post hoc ancestry adjustment method that can express the polygenic risk on the same scale across ancestrally diverse individuals and facilitate the clinical implementation of the PRS in prospective cohorts. Results The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined. The top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5-fold of increase in T2D risk, which corresponds to the increased risk of T2D for first-degree relatives. The post hoc ancestry adjustment method eliminated major distributional differences in the PRS across ancestries without compromising its predictive performance. Conclusions By integrating T2D GWAS from multiple populations, we developed and validated a trans-ancestry PRS, and demonstrated its potential as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

引用

页数：16

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