Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.
Rare variant analysis in eczema identifies exonic variants in DUSP1, NOTCH4 and SLC9A4.
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DOI：
10.1038/s41467-021-26783-x
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发表时间：
2021-11-16
影响因子：
16.6
通讯作者：
Lee YA
中科院分区：
文献类型：
--
作者：
Grosche S;Marenholz I;Esparza-Gordillo J;Arnau-Soler A;Pairo-Castineira E;Rüschendorf F;Ahluwalia TS;Almqvist C;Arnold A;Australian Asthma Genetics Consortium (AAGC);Baurecht H;Bisgaard H;Bønnelykke K;Brown SJ;Bustamante M;Curtin JA;Custovic A;Dharmage SC;Esplugues A;Falchi M;Fernandez-Orth D;Ferreira MAR;Franke A;Gerdes S;Gieger C;Hakonarson H;Holt PG;Homuth G;Hubner N;Hysi PG;Jarvelin MR;Karlsson R;Koppelman GH;Lau S;Lutz M;Magnusson PKE;Marks GB;Müller-Nurasyid M;Nöthen MM;Paternoster L;Pennell CE;Peters A;Rawlik K;Robertson CF;Rodriguez E;Sebert S;Simpson A;Sleiman PMA;Standl M;Stölzl D;Strauch K;Szwajda A;Tenesa A;Thompson PJ;Ullemar V;Visconti A;Vonk JM;Wang CA;Weidinger S;Wielscher M;Worth CL;Xu CJ;Lee YA
先前的全基因组关联研究揭示了与湿疹有关的多种常见变异，但罕见变异的作用仍有待阐明。在这里，我们研究了罕见变异在湿疹易感性中的作用。我们对 21 个研究人群进行了荟萃分析，其中包括 20,016 名湿疹病例和 380,433 名对照者。使用大量基于人群的参考面板对罕见变异进行高精度估算。我们发现 DUSP1、NOTCH4 和 SLC9A4 中罕见的外显子变异与湿疹相关。在 DUSP1 和 NOTCH4 中，错义变体预计会影响保守的功能域。此外，还发现了 SATB1-AS1/KCNH8、TRIB1/LINC00861、ZBTB1、TBX21/OSBPL7 和 CSF2RB 的五个新的常见变体。虽然基于罕见变异优先的基因在皮肤中显着上调，但常见变异指向免疫细胞功能。超过 20% 的基于单核苷酸变异的遗传力可归因于罕见和低频变异。位于功能蛋白结构域中的已鉴定的罕见/低频变异指出了湿疹新治疗方法的有希望的靶标。迄今为止，湿疹的遗传学研究主要探索常见的遗传变异。在这里，作者对常见和罕见的变异进行了大型荟萃分析，发现了 8 个与湿疹相关的位点。超过 20% 的疾病遗传力可归因于罕见变异。
Previous genome-wide association studies revealed multiple common variants involved in eczema but the role of rare variants remains to be elucidated. Here, we investigate the role of rare variants in eczema susceptibility. We meta-analyze 21 study populations including 20,016 eczema cases and 380,433 controls. Rare variants are imputed with high accuracy using large population-based reference panels. We identify rare exonic variants in DUSP1, NOTCH4, and SLC9A4 to be associated with eczema. In DUSP1 and NOTCH4 missense variants are predicted to impact conserved functional domains. In addition, five novel common variants at SATB1-AS1/KCNH8, TRIB1/LINC00861, ZBTB1, TBX21/OSBPL7, and CSF2RB are discovered. While genes prioritized based on rare variants are significantly up-regulated in the skin, common variants point to immune cell function. Over 20% of the single nucleotide variant-based heritability is attributable to rare and low-frequency variants. The identified rare/low-frequency variants located in functional protein domains point to promising targets for novel therapeutic approaches to eczema. Genetic studies of eczema to date have mostly explored common genetic variation. Here, the authors perform a large meta-analysis for common and rare variants and discover 8 loci associated with eczema. Over 20% of the heritability of the condition is attributable to rare variants.
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影响因子：
30.8
作者：
Ellinghaus D;Jostins L;Spain SL;Cortes A;Bethune J;Han B;Park YR;Raychaudhuri S;Pouget JG;Hübenthal M;Folseraas T;Wang Y;Esko T;Metspalu A;Westra HJ;Franke L;Pers TH;Weersma RK;Collij V;D'Amato M;Halfvarson J;Jensen AB;Lieb W;Degenhardt F;Forstner AJ;Hofmann A;International IBD Genetics Consortium (IIBDGC);International Genetics of Ankylosing Spondylitis Consortium (IGAS);International PSC Study Group (IPSCSG);Genetic Analysis of Psoriasis Consortium (GAPC);Psoriasis Association Genetics Extension (PAGE);Schreiber S;Mrowietz U;Juran BD;Lazaridis KN;Brunak S;Dale AM;Trembath RC;Weidinger S;Weichenthal M;Ellinghaus E;Elder JT;Barker JN;Andreassen OA;McGovern DP;Karlsen TH;Barrett JC;Parkes M;Brown MA;Franke A
通讯作者：
Franke A
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
DOI：
10.1126/science.1262110
发表时间：
2015-05-08
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
GTEx Consortium
通讯作者：
GTEx Consortium
影响因子：
16.8
作者：
通讯作者：
--
影响因子：
4.4
作者：
Li, LH;Huang, GM;Hood, L
通讯作者：
Hood, L