Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders.
Expression quantitative trait loci in the developing human brain and their enrichment in neuropsychiatric disorders.
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DOI：
10.1186/s13059-018-1567-1
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发表时间：
2018-11-12
期刊：
影响因子：
12.3
通讯作者：
Bray NJ
中科院分区：
文献类型：
--
作者：
O'Brien HE;Hannon E;Hill MJ;Toste CC;Robertson MJ;Morgan JE;McLaughlin G;Lewis CM;Schalkwyk LC;Hall LS;Pardiñas AF;Owen MJ;O'Donovan MC;Mill J;Bray NJ
基因对人类胎儿大脑基因表达的影响似乎会影响出生后大脑的各种相关特征，包括神经精神障碍的易感性。然而，到目前为止，还没有研究定位到人类产前大脑全基因组表达的数量性状基因座(EQTL)。我们对妊娠中期的120个人脑进行了深入的RNA测序和全基因组基因分型，以提供第一个专门来自人类胎儿大脑的eQTL数据集。我们在个体转录本和整个基因水平上发现了高度可信的顺式作用eQTL，包括对染色体17q21上常见的倒位多态的许多定位。胎儿大脑eQTL在包括注意力缺陷多动障碍、精神分裂症和双相情感障碍在内的出生后疾病的风险变量中丰富。我们进一步确定了产前大脑中可能介导神经精神特征风险的基因表达的变化，包括与精神分裂症遗传风险相关的C4a表达增加，与双相情感障碍遗传风险相关的LRRC57表达增加，以及与影响神经质个性特征的变异相关的染色体17q21倒位内多个基因表达的变化。我们已经绘制了在人类胎儿大脑中运行的eQTL图，提供了证据表明这些基因增加了某些神经精神疾病的风险，并确定了可能介导这些疾病易感性的基因表达变化。本文的在线版本(10.1186/s13059-0181567-1)包含补充材料，可供授权用户使用。
Genetic influences on gene expression in the human fetal brain plausibly impact upon a variety of postnatal brain-related traits, including susceptibility to neuropsychiatric disorders. However, to date, there have been no studies that have mapped genome-wide expression quantitative trait loci (eQTL) specifically in the human prenatal brain. We performed deep RNA sequencing and genome-wide genotyping on a unique collection of 120 human brains from the second trimester of gestation to provide the first eQTL dataset derived exclusively from the human fetal brain. We identify high confidence cis-acting eQTL at the individual transcript as well as whole gene level, including many mapping to a common inversion polymorphism on chromosome 17q21. Fetal brain eQTL are enriched among risk variants for postnatal conditions including attention deficit hyperactivity disorder, schizophrenia, and bipolar disorder. We further identify changes in gene expression within the prenatal brain that potentially mediate risk for neuropsychiatric traits, including increased expression of C4A in association with genetic risk for schizophrenia, increased expression of LRRC57 in association with genetic risk for bipolar disorder, and altered expression of multiple genes within the chromosome 17q21 inversion in association with variants influencing the personality trait of neuroticism. We have mapped eQTL operating in the human fetal brain, providing evidence that these confer risk to certain neuropsychiatric disorders, and identifying gene expression changes that potentially mediate susceptibility to these conditions. The online version of this article (10.1186/s13059-018-1567-1) contains supplementary material, which is available to authorized users.
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影响因子：
64.5
作者：
de la Torre-Ubieta L;Stein JL;Won H;Opland CK;Liang D;Lu D;Geschwind DH
通讯作者：
Geschwind DH
遗传对人体组织基因表达的影响。
影响因子：
64.8
作者：
GTEx Consortium;Laboratory, Data Analysis &Coordinating Center (LDACC)—Analysis Working Group;Statistical Methods groups—Analysis Working Group;Enhancing GTEx (eGTEx) groups;NIH Common Fund;NIH/NCI;NIH/NHGRI;NIH/NIMH;NIH/NIDA;Biospecimen Collection Source Site—NDRI;Biospecimen Collection Source Site—RPCI;Biospecimen Core Resource—VARI;Brain Bank Repository—University of Miami Brain Endowment Bank;Leidos Biomedical—Project Management;ELSI Study;Genome Browser Data Integration &Visualization—EBI;Genome Browser Data Integration &Visualization—UCSC Genomics Institute, University of California Santa Cruz;Lead analysts:;Laboratory, Data Analysis &Coordinating Center (LDACC):;NIH program management:;Biospecimen collection:;Pathology:;eQTL manuscript working group:;Battle A;Brown CD;Engelhardt BE;Montgomery SB
通讯作者：
Montgomery SB
影响因子：
4.4
作者：
de Jong S;Chepelev I;Janson E;Strengman E;van den Berg LH;Veldink JH;Ophoff RA
通讯作者：
Ophoff RA
影响因子：
7.7
作者：
Gutierrez-Arcelus M;Lappalainen T;Montgomery SB;Buil A;Ongen H;Yurovsky A;Bryois J;Giger T;Romano L;Planchon A;Falconnet E;Bielser D;Gagnebin M;Padioleau I;Borel C;Letourneau A;Makrythanasis P;Guipponi M;Gehrig C;Antonarakis SE;Dermitzakis ET
通讯作者：
Dermitzakis ET
影响因子：
25
作者：
Hannon E;Spiers H;Viana J;Pidsley R;Burrage J;Murphy TM;Troakes C;Turecki G;O'Donovan MC;Schalkwyk LC;Bray NJ;Mill J
通讯作者：
Mill J