Integrative Genetic and Epigenetic Analysis Uncovers Regulatory Mechanisms of Autoimmune Disease

被引：24

作者：

Shooshtari, Parisa ^{[1
,2
,3
]}

Huang, Hailiang ^{[2
,3
,4
,5
]}

Cotsapas, Chris ^{[1
,2
,3
,6
]}

机构：

[1] Yale Sch Med, Dept Neurol, New Haven, CT 06511 USA

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

[3] Broad Inst Harvard & MIT, Stanley Ctr Psychiat Res, Cambridge, MA 02142 USA

[4] Massachusetts Gen Hosp, Dept Med, Analyt & Translat Genet Unit, Boston, MA 02114 USA

[5] Harvard Med Sch, Boston, MA 02114 USA

[6] Yale Sch Med, Dept Genet, New Haven, CT 06520 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2017年 / 101卷 / 01期

关键词：

INFLAMMATORY-BOWEL-DISEASE; PRIMARY BILIARY-CIRRHOSIS; GENOME-WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; MULTIPLE-SCLEROSIS; CELL-TYPES; PARTITIONING HERITABILITY; VARIANTS; COMMON; PATTERNS;

D O I：

10.1016/j.ajhg.2017.06.001

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Genome-wide association studies in autoimmune and inflammatory diseases (AID) have uncovered hundreds of loci mediating risk. These associations are preferentially located in non-coding DNA regions and in particular in tissue-specific DNase I hypersensitivity sites (DHSs). While these analyses clearly demonstrate the overall enrichment of disease risk alleles on gene regulatory regions, they are not designed to identify individual regulatory regions mediating risk or the genes under their control, and thus uncover the specific molecular events driving disease risk. To do so we have departed from standard practice by identifying regulatory regions which replicate across samples and connect them to the genes they control through robust re-analysis of public data. We find significant evidence of regulatory potential in 78/301 (26%) risk loci across nine autoimmune and inflammatory diseases, and we find that individual genes are targeted by these effects in 53/78 (68%) of these. Thus, we are able to generate testable mechanistic hypotheses of the molecular changes that drive disease risk.

引用

页码：75 / 86

页数：12

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