Improving the trans-ancestry portability of polygenic risk scores by prioritizing variants in predicted cell-type-specific regulatory elements

被引：105

作者：

Amariuta, Tiffany ^{[1
,2
,3
,4
,5
,6
]}

Ishigaki, Kazuyoshi ^{[1
,2
,3
,4
,7
]}

Sugishita, Hiroki ^{[8
]}

Ohta, Tazro ^{[9
,10
]}

Koido, Masaru ^{[7
,11
]}

Dey, Kushal K. ^{[12
]}

Matsuda, Koichi ^{[13
,14
]}

Murakami, Yoshinori ^{[11
]}

Price, Alkes L. ^{[4
,12
,15
]}

Kawakami, Eiryo ^{[9
,16
]}

Terao, Chikashi ^{[7
,17
,18
]}

Raychaudhuri, Soumya ^{[1
,2
,3
,4
,5
,19
]}

机构：

[1] Harvard Med Sch, Ctr Data Sci, Boston, MA 02115 USA

[2] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Genet, Boston, MA 02115 USA

[3] Harvard Med Sch, Brigham & Womens Hosp, Dept Med, Div Rheumatol, Boston, MA 02115 USA

[4] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA

[5] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA

[6] Harvard Univ, Grad Sch Arts & Sci, Cambridge, MA 02138 USA

[7] RIKEN, Lab Stat & Translat Genet, Ctr Integrat Med Sci, Yokohama, Kanagawa, Japan

[8] RIKEN, Lab Dev Genet, Ctr Integrat Med Sci IMS, Yokohama, Kanagawa, Japan

[9] RIKEN, Med Sci Innovat Hub Program, Yokohama, Kanagawa, Japan

[10] Res Org Informat & Syst, Joint Support Ctr Data Sci Res, Database Ctr Life Sci, Shizuoka, Japan

[11] Univ Tokyo, Inst Med Sci, Div Mol Pathol, Tokyo, Japan

[12] Harvard TH Chan Sch Publ Hlth, Dept Epidemiol, Boston, MA USA

[13] Univ Tokyo, Human Genome Ctr, Inst Med Sci, Lab Genome Technol, Tokyo, Japan

[14] Univ Tokyo, Grad Sch Frontier Sci, Dept Computat Biol & Med Sci, Lab Clin Genome Sequencing, Tokyo, Japan

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

[16] Chiba Univ, Grad Sch Med, Artificial Intelligence Med, Chiba, Japan

[17] Shizuoka Prefectural Gen Hosp, Clin Res Ctr, Shizuoka, Japan

[18] Univ Shizuoka, Sch Pharmaceut Sci, Dept Appl Genet, Shizuoka, Japan

[19] Univ Manchester, Manchester Acad Hlth Sci Ctr, Ctr Genet & Genom Versus Arthrit, Ctr Musculoskeletal Res, Manchester, Lancs, England

来源：

NATURE GENETICS | 2020年 / 52卷 / 12期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

GENOME-WIDE ASSOCIATION; HERITABILITY; ANNOTATION; ARCHITECTURE; ENRICHMENT;

D O I：

10.1038/s41588-020-00740-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Poor trans-ancestry portability of polygenic risk scores is a consequence of Eurocentric genetic studies and limited knowledge of shared causal variants. Leveraging regulatory annotations may improve portability by prioritizing functional over tagging variants. We constructed a resource of 707 cell-type-specific IMPACT regulatory annotations by aggregating 5,345 epigenetic datasets to predict binding patterns of 142 transcription factors across 245 cell types. We then partitioned the common SNP heritability of 111 genome-wide association study summary statistics of European (average n approximate to 189,000) and East Asian (average n approximate to 157,000) origin. IMPACT annotations captured consistent SNP heritability between populations, suggesting prioritization of shared functional variants. Variant prioritization using IMPACT resulted in increased trans-ancestry portability of polygenic risk scores from Europeans to East Asians across all 21 phenotypes analyzed (49.9% mean relative increase in R-2). Our study identifies a crucial role for functional annotations such as IMPACT to improve the trans-ancestry portability of genetic data. A resource of cell-type-specific IMPACT regulatory annotations improves the trans-ancestry portability of polygenic risk scores by prioritizing variants enriched for trait heritability.

引用

页码：1346 / 1354

页数：9

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