Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
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DOI：
10.1038/s41588-018-0059-2
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发表时间：
2018-03
期刊：
影响因子：
30.8
通讯作者：
Walters JTR
中科院分区：
文献类型：
--
作者：
Pardiñas AF;Holmans P;Pocklington AJ;Escott-Price V;Ripke S;Carrera N;Legge SE;Bishop S;Cameron D;Hamshere ML;Han J;Hubbard L;Lynham A;Mantripragada K;Rees E;MacCabe JH;McCarroll SA;Baune BT;Breen G;Byrne EM;Dannlowski U;Eley TC;Hayward C;Martin NG;McIntosh AM;Plomin R;Porteous DJ;Wray NR;Caballero A;Geschwind DH;Huckins LM;Ruderfer DM;Santiago E;Sklar P;Stahl EA;Won H;Agerbo E;Als TD;Andreassen OA;Bækvad-Hansen M;Mortensen PB;Pedersen CB;Børglum AD;Bybjerg-Grauholm J;Djurovic S;Durmishi N;Pedersen MG;Golimbet V;Grove J;Hougaard DM;Mattheisen M;Molden E;Mors O;Nordentoft M;Pejovic-Milovancevic M;Sigurdsson E;Silagadze T;Hansen CS;Stefansson K;Stefansson H;Steinberg S;Tosato S;Werge T;GERAD1 Consortium;CRESTAR Consortium;Collier DA;Rujescu D;Kirov G;Owen MJ;O'Donovan MC;Walters JTR
精神分裂症是一种使人衰弱的精神疾病，通常与生活质量差和预期寿命缩短有关。尽管大规模基因组研究已经开始提供见解，但在改善治疗结果方面缺乏进展是由于对基础生物学的了解有限。我们报告了一项新的精神分裂症全基因组关联研究（11，260例病例和24，542例对照），通过对现有数据的荟萃分析，我们确定了50个新的相关位点，共145个位点。通过整合基因组精细定位与脑表达和染色体构象数据，我们确定了33个位点内的候选致病基因。我们还首次表明，在强选择压力下的基因中，共同的变异关联信号高度富集。这些发现为精神分裂症的生物学和遗传结构提供了新的见解，突出了突变不耐受基因的重要性，并提出了一种常见风险变异在人群中持续存在的机制。
Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
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影响因子：
2.1
作者：
Dudbridge F
通讯作者：
Dudbridge F
影响因子：
30.8
作者：
Bulik-Sullivan, Brendan K.;Loh, Po-Ru;Finucane, Hilary K.;Ripke, Stephan;Yang, Jian;Patterson, Nick;Daly, Mark J.;Price, Alkes L.;Neale, Benjamin M.
通讯作者：
Neale, Benjamin M.
影响因子：
4.3
作者：
Batada NN;Hurst LD;Tyers M
通讯作者：
Tyers M
影响因子：
30.8
作者：
Finucane HK;Bulik-Sullivan B;Gusev A;Trynka G;Reshef Y;Loh PR;Anttila V;Xu H;Zang C;Farh K;Ripke S;Day FR;ReproGen Consortium;Schizophrenia Working Group of the Psychiatric Genomics Consortium;RACI Consortium;Purcell S;Stahl E;Lindstrom S;Perry JR;Okada Y;Raychaudhuri S;Daly MJ;Patterson N;Neale BM;Price AL
通讯作者：
Price AL
影响因子：
9.9
作者：
Fernandez, Esperanza;Collins, Mark O.;Uren, Rachel T.;Kopanitsa, Maksym V.;Komiyama, Noboru H.;Croning, Mike D. R.;Zografos, Lysimachos;Armstrong, J. Douglas;Choudhary, Jyoti S.;Grant, Seth G. N.
通讯作者：
Grant, Seth G. N.