Influence of autozygosity on common disease risk across the phenotypic spectrum.
Influence of autozygosity on common disease risk across the phenotypic spectrum.
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DOI：
10.1016/j.cell.2023.08.028
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发表时间：
2023-10-12
期刊：
影响因子：
64.5
通讯作者：
Martin, Hilary C.
中科院分区：
文献类型：
--
作者：
Malawsky, Daniel S.;van Walree, Eva;Jacobs, Benjamin M.;Heng, Teng Hiang;Huang, Qin Qin;Sabir, Ataf H.;Rahman, Saadia;Sharif, Saghira Malik;Khan, Ahsan;Mirkov, Masa Umicevic;Kuwahara, Hiroyuki;Gao, Xin;Alkuraya, Fowzan S.;Posthuma, Danielle;Newman, William G.;Griffiths, Christopher J.;Mathur, Rohini;van Heel, David A.;Finer, Sarah;O'Connell, Jared;Martin, Hilary C.
自合性与罕见的孟德尔疾病和临床相关的数量性状有关。我们在 Genes & Health（n = 23,978 英国南亚人）、UK Biobank（n = 397,184）和 23andMe 中研究了纯合性运行 (FROH) 中基因组部分与常见疾病之间的关联。我们表明，将分析限制于第一代表兄弟姐妹的后代是减少由于 FROH 的社会/环境相关性而造成的混杂的有效方法。在 G&H+UK Biobank 的这一组中，我们发现 FROH 与 12 种常见疾病之间存在整个实验范围内的显着关联。我们通过 23andMe 中的兄弟姐妹内分析复制了与 2 型糖尿病 (T2D) 和创伤后应激障碍的关联（中位数 n = 480,282）。我们估计，英籍巴基斯坦人中 5%–18% 的 T2D 病例是由近亲血亲导致的自合子造成的。我们的工作强调了常见疾病广泛的非加性遗传效应的可能性，并对全球近亲率高的人群具有重要意义。减少自合性-表型关联研究中混杂因素的可靠方法 较高的自合性与 T2D 等常见疾病的风险增加相关 复制研究结果，包括兄弟姐妹内分析 血缘关系解释了英国巴基斯坦人约 10% 的 T2D 病例 由血缘关系引起的自合性与多种复杂疾病（包括 2 型糖尿病）存在因果关系。
Autozygosity is associated with rare Mendelian disorders and clinically relevant quantitative traits. We investigated associations between the fraction of the genome in runs of homozygosity (FROH) and common diseases in Genes & Health (n = 23,978 British South Asians), UK Biobank (n = 397,184), and 23andMe. We show that restricting analysis to offspring of first cousins is an effective way of reducing confounding due to social/environmental correlates of FROH. Within this group in G&H+UK Biobank, we found experiment-wide significant associations between FROH and twelve common diseases. We replicated associations with type 2 diabetes (T2D) and post-traumatic stress disorder via within-sibling analysis in 23andMe (median n = 480,282). We estimated that autozygosity due to consanguinity accounts for 5%–18% of T2D cases among British Pakistanis. Our work highlights the possibility of widespread non-additive genetic effects on common diseases and has important implications for global populations with high rates of consanguinity. Robust method to reduce confounding in autozygosity-phenotype association studies Higher autozygosity associated with increased risk for common diseases such as T2D Replication of findings including a within-sibling analysis Consanguinity explains ∼10% of T2D cases in British Pakistanis Autozygosity resulting from consanguinity is causally associated with several complex diseases, including type 2 diabetes.
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影响因子：
64.8
作者：
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：
2.6
作者：
Abdellaoui, Abdel;Hottenga, Jouke-Jan;Xiao, Xiangjun;Scheet, Paul;Ehli, Erik A.;Davies, Gareth E.;Hudziak, James J.;Smit, Dirk J. A.;Bartels, Meike;Willemsen, Gonneke;Brooks, Andrew;Sullivan, Patrick F.;Smit, Johannes H.;de Geus, Eco J.;Penninx, Brenda W. J. H.;Boomsma, Dorret I.
通讯作者：
Boomsma, Dorret I.
影响因子：
7
作者：
Basu, A;Mukherjee, N;Majumder, PP
通讯作者：
Majumder, PP
影响因子：
14.9
作者：
Fairley, Susan;Lowy-Gallego, Ernesto;Flicek, Paul
通讯作者：
Flicek, Paul
影响因子：
4.5
作者：
Keller MC;Simonson MA;Ripke S;Neale BM;Gejman PV;Howrigan DP;Lee SH;Lencz T;Levinson DF;Sullivan PF;Schizophrenia Psychiatric Genome-Wide Association Study Consortium
通讯作者：
Schizophrenia Psychiatric Genome-Wide Association Study Consortium