Polymorphic short tandem repeats make widespread contributions to blood and serum traits.
Polymorphic short tandem repeats make widespread contributions to blood and serum traits.
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多态短串联重复序列对血液和血清性状有广泛的影响。
DOI：
10.1016/j.xgen.2023.100458
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发表时间：
2023-12-13
期刊：
影响因子：
--
通讯作者：
Gymrek, Melissa
中科院分区：
文献类型：
--
作者：
Margoliash, Jonathan;Fuchs, Shai;Li, Yang;Zhang, Xuan;Massarat, Arya;Goren, Alon;Gymrek, Melissa
短串联重复序列（STR）是由1-6 bp的连续重复序列组成的基因组区域。基于单核苷酸多态性（SNP）的全基因组关联研究（GWAS）不能完全捕获STR效应。为了研究这些影响，我们将445，720个STR输入到来自408，153名白色英国生物银行参与者的基因型阵列中，并测试与44种血液表型的关联。使用两种精细映射方法，我们确定了119个候选的因果STR-性状关联，并估计STR占这些性状的GWAS可识别的因果变异的5.2%-7.6%。这些是多种表型的最强关联，包括与载脂蛋白B水平相关的编码CTG重复，与血小板性状相关的启动子CGG重复，以及与平均血小板体积相关的内含子poly（A）重复。我们的研究表明，STR对复杂的性状做出了广泛的贡献，提供了严格选择的候选因果STR，并证明了需要考虑更完整的GWAS遗传变异的观点。一种新的框架能够将短串联重复序列变异纳入GWAS短串联重复序列占血液性状候选致病变异的5. 2%-7. 6%严格的精细定位鉴定了119种候选致病重复序列-性状关联将重复序列纳入未来的GWAS可能揭示新的致病变异Margoliash等人提出了一种框架，用于包括短串联重复序列（STR）复杂性状分析中的遗传变异。使用两种精细映射方法，他们估计STR占所研究性状可识别的因果变异的5.2%-7.6%，并突出了119个候选因果STR-性状关联，解决了多个表型的一些最强关联。这项研究表明，STR在复杂性状中发挥着重要作用，并表明需要在全基因组关联研究中包括一套更完整的遗传变异。
Short tandem repeats (STRs) are genomic regions consisting of repeated sequences of 1–6 bp in succession. Single-nucleotide polymorphism (SNP)-based genome-wide association studies (GWASs) do not fully capture STR effects. To study these effects, we imputed 445,720 STRs into genotype arrays from 408,153 White British UK Biobank participants and tested for association with 44 blood phenotypes. Using two fine-mapping methods, we identify 119 candidate causal STR-trait associations and estimate that STRs account for 5.2%–7.6% of causal variants identifiable from GWASs for these traits. These are among the strongest associations for multiple phenotypes, including a coding CTG repeat associated with apolipoprotein B levels, a promoter CGG repeat with platelet traits, and an intronic poly(A) repeat with mean platelet volume. Our study suggests that STRs make widespread contributions to complex traits, provides stringently selected candidate causal STRs, and demonstrates the need to consider a more complete view of genetic variation in GWASs. A novel framework enables incorporating short tandem repeat variants into GWASs Short tandem repeats comprise 5.2%–7.6% of candidate causal variants for blood traits Stringent fine-mapping identifies 119 candidate causal repeat-trait associations Incorporation of repeats into future GWASs is likely to reveal novel causal variants Margoliash et al. produce a framework for including short tandem repeat (STR) genetic variants in complex trait analysis. Using two fine-mapping methods, they estimate that STRs account for 5.2%–7.6% of causal variants identifiable for the studied traits and highlight 119 candidate causal STR-trait associations, resolving some of the strongest associations for multiple phenotypes. This study suggests that STRs play an important role in complex traits and demonstrates the need to include a more complete set of genetic variation in genome-wide association studies.
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影响因子：
14.9
作者：
Frankish A;Diekhans M;Ferreira AM;Johnson R;Jungreis I;Loveland J;Mudge JM;Sisu C;Wright J;Armstrong J;Barnes I;Berry A;Bignell A;Carbonell Sala S;Chrast J;Cunningham F;Di Domenico T;Donaldson S;Fiddes IT;García Girón C;Gonzalez JM;Grego T;Hardy M;Hourlier T;Hunt T;Izuogu OG;Lagarde J;Martin FJ;Martínez L;Mohanan S;Muir P;Navarro FCP;Parker A;Pei B;Pozo F;Ruffier M;Schmitt BM;Stapleton E;Suner MM;Sycheva I;Uszczynska-Ratajczak B;Xu J;Yates A;Zerbino D;Zhang Y;Aken B;Choudhary JS;Gerstein M;Guigó R;Hubbard TJP;Kellis M;Paten B;Reymond A;Tress ML;Flicek P
通讯作者：
Flicek P
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
64.8
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Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
影响因子：
30.8
作者：
Boettger, Linda M.;Salem, Rany M.;McCarroll, Steven A.
通讯作者：
McCarroll, Steven A.
影响因子：
9.8
作者：
Browning, Brian L.;Zhou, Ying;Browning, Sharon R.
通讯作者：
Browning, Sharon R.