How rare and common risk variation jointly affect liability for autism spectrum disorder.
How rare and common risk variation jointly affect liability for autism spectrum disorder.
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罕见和常见的风险变异如何共同影响自闭症谱系障碍的责任。
DOI：
10.1186/s13229-021-00466-2
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发表时间：
2021-10-06
期刊：
影响因子：
6.2
通讯作者：
Devlin B
中科院分区：
文献类型：
--
作者：
Klei L;McClain LL;Mahjani B;Panayidou K;De Rubeis S;Grahnat AS;Karlsson G;Lu Y;Melhem N;Xu X;Reichenberg A;Sandin S;Hultman CM;Buxbaum JD;Roeder K;Devlin B
遗传研究表明，自闭症谱系障碍（ASD）的倾向性存在罕见和常见的变异。在发现的风险变异中，那些在人群中罕见的变异总是对责任有很大的影响，而常见的变异影响很小。然而，总的来说，常见的风险变异占人口水平变异的大部分。这些罕见和常见的风险变异如何共同影响个人的责任需要进一步研究。为了探索常见和罕见变异如何共同影响责任，我们评估了两个以罕见和常见遗传变异为特征的ASD家族队列（Simons Simplex Collection和基于人群的自闭症遗传和环境研究）。我们分析了来自3011名受影响受试者的数据，以及两组以共同遗传变异为特征的未受影响个体的数据：3011名受试者的祖先与ASD受试者相匹配，11950名受试者用于估计等位基因频率。我们使用遗传评分来评估影响ASD风险的常见遗传变异的相对负担（以下简称“负担”），并确定这种负担如何在三个亚人群中分布：携带与ASD风险相关的潜在破坏性变异的ASD受试者（“PDV携带者”）；没有ASD的受试者（“非携带者”）；而未受影响的受试者被认为是非携带者。ASD受试者的负担随机大于对照组。对于PDV携带者，他们的平均负担介于非携带者和对照组之间。携带者和非携带者ASD患者的平均负担均高于对照组。常见和罕见变异的影响可能加在一起决定个人层面的责任。只有305名ASD受试者是已知的PDV携带者。这一相对较小的亚群限制了本研究对一般负担模式的描述，而不是特定pdv或基因的影响。此外，一小部分被归类为非携带者的受试者可能是PDV携带者。常见和罕见风险变异引起的责任可能加在一起决定任何被诊断为ASD的个体的风险。平均而言，ASD受试者承担着共同风险变异的巨大负担，即使他们也携带着罕见的PDV影响风险。在线版本包含补充材料，可在10.1186/s13229-021-00466-2获得。
Genetic studies have implicated rare and common variations in liability for autism spectrum disorder (ASD). Of the discovered risk variants, those rare in the population invariably have large impact on liability, while common variants have small effects. Yet, collectively, common risk variants account for the majority of population-level variability. How these rare and common risk variants jointly affect liability for individuals requires further study. To explore how common and rare variants jointly affect liability, we assessed two cohorts of ASD families characterized for rare and common genetic variations (Simons Simplex Collection and Population-Based Autism Genetics and Environment Study). We analyzed data from 3011 affected subjects, as well as two cohorts of unaffected individuals characterized for common genetic variation: 3011 subjects matched for ancestry to ASD subjects and 11,950 subjects for estimating allele frequencies. We used genetic scores, which assessed the relative burden of common genetic variation affecting risk of ASD (henceforth “burden”), and determined how this burden was distributed among three subpopulations: ASD subjects who carry a potentially damaging variant implicated in risk of ASD (“PDV carriers”); ASD subjects who do not (“non-carriers”); and unaffected subjects who are assumed to be non-carriers. Burden harbored by ASD subjects is stochastically greater than that harbored by control subjects. For PDV carriers, their average burden is intermediate between non-carrier ASD and control subjects. Both carrier and non-carrier ASD subjects have greater burden, on average, than control subjects. The effects of common and rare variants likely combine additively to determine individual-level liability. Only 305 ASD subjects were known PDV carriers. This relatively small subpopulation limits this study to characterizing general patterns of burden, as opposed to effects of specific PDVs or genes. Also, a small fraction of subjects that are categorized as non-carriers could be PDV carriers. Liability arising from common and rare risk variations likely combines additively to determine risk of any individual diagnosed with ASD. On average, ASD subjects carry a substantial burden of common risk variation, even if they also carry a rare PDV affecting risk. The online version contains supplementary material available at 10.1186/s13229-021-00466-2.
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影响因子：
6.2
作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
通讯作者：
Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
64.8
作者：
Iossifov, Ivan;O'Roak, Brian J.;Sanders, Stephan J.;Ronemus, Michael;Krumm, Niklas;Levy, Dan;Stessman, Holly A.;Witherspoon, Kali T.;Vives, Laura;Patterson, Karynne E.;Smith, Joshua D.;Paeper, Bryan;Nickerson, Deborah A.;Dea, Jeanselle;Dong, Shan;Gonzalez, Luis E.;Mandell, Jeffrey D.;Mane, Shrikant M.;Murtha, Michael T.;Sullivan, Catherine A.;Walker, Michael F.;Waqar, Zainulabedin;Wei, Liping;Willsey, A. Jeremy;Yamrom, Boris;Lee, Yoon-ha;Grabowska, Ewa;Dalkic, Ertugrul;Wang, Zihua;Marks, Steven;Andrews, Peter;Leotta, Anthony;Kendall, Jude;Hakker, Inessa;Rosenbaum, Julie;Ma, Beicong;Rodgers, Linda;Troge, Jennifer;Narzisi, Giuseppe;Yoon, Seungtai;Schatz, Michael C.;Ye, Kenny;McCombie, W. Richard;Shendure, Jay;Eichler, Evan E.;State, Matthew W.;Wigler, Michael
通讯作者：
Wigler, Michael
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：
56.9
作者：
An, Joon-Yong;Lin, Kevin;Sanders, Stephan J.
通讯作者：
Sanders, Stephan J.