TY - JOUR
T1 - Development and validation of a trans-ancestry polygenic risk score for type 2 diabetes in diverse populations
AU - Ge, Tian
AU - Irvin, Marguerite R.
AU - Patki, Amit
AU - Srinivasasainagendra, Vinodh
AU - Lin, Yen Feng
AU - Tiwari, Hemant K.
AU - Armstrong, Nicole D.
AU - Benoit, Barbara
AU - Chen, Chia Yen
AU - Choi, Karmel W.
AU - Cimino, James J.
AU - Davis, Brittney H.
AU - Dikilitas, Ozan
AU - Etheridge, Bethany
AU - Feng, Yen Chen Anne
AU - Gainer, Vivian
AU - Huang, Hailiang
AU - Jarvik, Gail P.
AU - Kachulis, Christopher
AU - Kenny, Eimear E.
AU - Khan, Atlas
AU - Kiryluk, Krzysztof
AU - Kottyan, Leah
AU - Kullo, Iftikhar J.
AU - Lange, Christoph
AU - Lennon, Niall
AU - Leong, Aaron
AU - Malolepsza, Edyta
AU - Miles, Ayme D.
AU - Murphy, Shawn
AU - Namjou, Bahram
AU - Narayan, Renuka
AU - O’Connor, Mark J.
AU - Pacheco, Jennifer A.
AU - Perez, Emma
AU - Rasmussen-Torvik, Laura J.
AU - Rosenthal, Elisabeth A.
AU - Schaid, Daniel
AU - Stamou, Maria
AU - Udler, Miriam S.
AU - Wei, Wei Qi
AU - Weiss, Scott T.
AU - Ng, Maggie C.Y.
AU - Smoller, Jordan W.
AU - Lebo, Matthew S.
AU - Meigs, James B.
AU - Limdi, Nita A.
AU - Karlson, Elizabeth W.
N1 - Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Clinical implementation
KW - Diverse populations
KW - Polygenic risk score
KW - Type 2 diabetes
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U2 - 10.1186/s13073-022-01074-2
DO - 10.1186/s13073-022-01074-2
M3 - Article
C2 - 35765100
AN - SCOPUS:85133024033
SN - 1756-994X
VL - 14
JO - Genome medicine
JF - Genome medicine
IS - 1
M1 - 70
ER -