Ultrarare Coding Variants and Cognitive Function in Schizophrenia.
Ultrarare Coding Variants and Cognitive Function in Schizophrenia.
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DOI：
10.1001/jamapsychiatry.2022.2289
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发表时间：
2022-10-01
期刊：
影响因子：
25.8
通讯作者：
Owen, Michael J.
中科院分区：
文献类型：
--
作者：
Creeth, Hugo D. J.;Rees, Elliott;Legge, Sophie E.;Dennison, Charlotte A.;Holmans, Peter;Walters, James T. R.;O'Donovan, Michael C.;Owen, Michael J.
在诊断为精神分裂症的个体中，超等位基因限制性变异（URCV）是否与认知功能降低相关？在这项对802名接受外显子组测序和认知测试的精神分裂症患者进行的病例内遗传关联研究中，发现携带URCV的个体认知功能显著降低。这项研究发现，URCV与精神分裂症患者的一般认知功能降低有关;通过更好地注释致病变异，基因组数据可能有助于识别那些具有特别高的认知障碍风险的精神分裂症患者，其中可以实施早期补救或预防措施。精神分裂症患者的认知功能受损与不良功能结局相关，但罕见编码变异的作用尚不清楚。目的：探讨超等位基因限制性变异体（URCV）是否与精神分裂症患者的认知功能相关。使用线性回归进行URCV与当前认知和病前认知能力的病例内遗传关联研究。对URCV、精神分裂症多基因风险评分、智力多基因风险评分和精神分裂症相关拷贝数变异对认知能力的影响进行多变量线性回归分析。使用精神分裂症共识认知成套测验中提高认知的测量和治疗研究来评估来自802名精神分裂症参与者的外显子组测序数据，并使用全国成人阅读测试来评估病前智商。这些人是从英国的临床和志愿精神卫生服务机构招募的。那些被诊断患有智力残疾或已知影响认知的神经系统疾病的人被排除在外。数据收集发生在2007年至2015年之间。数据分析时间为2020年4月至2022年3月。URCV、当前认知和经病前IQ校正的当前认知之间的相关性在802名参与者中，499名（62%）为男性，303名（38%）为女性;访谈时的平均（SD）年龄为43.36（11.87）岁。超保守型变异（n = 400）与较低的当前认知评分相关（β =-0.18; SE = 0.07; P = 0.005）。在单变量分析中，病前智商与URCV相关（β =-0.12; SE = 0.05; P = 0.02），与当前认知的相关性部分减弱（β =-0.09; SE = 0.05; P = 0.08）。多变量分析显示，测量的遗传因素组合解释了当前认知的6.2%方差，病前智商的10.3%方差，并支持与当前认知相关的URCV的结果独立于病前智商（β =-0.10; SE = 0.05; P = 0.03）。这项研究的结果表明，URCV有助于精神分裂症的认知功能的变化，部分独立的协会之前和之后的疾病发作。虽然估计的效应量很小，但未来的研究可能表明，随着致病性变异的更好注释，效应量将更大。基因组数据可能有助于确定那些认知障碍风险特别高的人，可以对其实施早期补救或预防措施。这项遗传关联研究评估了罕见的编码变异是否与精神分裂症患者当前的认知功能相关。
Are ultrarare constrained variants (URCVs) associated with reduced cognitive function in individuals diagnosed with schizophrenia? In this within-case genetic association study of 802 individuals with schizophrenia who had undergone exome sequencing and cognitive testing, significantly reduced cognitive function was found in individuals carrying URCVs. This study found that URCVs were associated with reduced general cognitive function in schizophrenia; with better annotation of pathogenic variants, genomic data may contribute to identifying those with schizophrenia at particularly high risk of cognitive impairment in whom early remedial or preventative measures can be implemented. Impaired cognitive function in schizophrenia is associated with poor functional outcomes, but the role of rare coding variants is unclear. To determine whether ultrarare constrained variants (URCVs) are associated with cognition in patients with schizophrenia. Linear regression was used to perform a within-case genetic association study of URCVs and current cognition and premorbid cognitive ability. A multivariable linear regression analysis of the outcomes associated with URCVs, schizophrenia polygenic risk score, polygenic risk score for intelligence and schizophrenia associated copy number variants on cognitive ability was performed. Exome sequencing data from 802 participants with schizophrenia were assessed for current cognition using the Measurement and Treatment Research to Improve Cognition in Schizophrenia Consensus Cognitive Battery and for estimated premorbid IQ using the National Adult Reading Test. Individuals were recruited from clinical and voluntary mental health services in the UK. Those with a diagnosis of intellectual disability or a neurological disorder known to affect cognition were excluded. Data collection occurred between 2007 and 2015. Data were analyzed between April 2020 and March 2022. Association between URCVs, current cognition, and current cognition adjusted for premorbid IQ. Of the 802 participants, 499 (62%) were men and 303 (38%) were women; mean (SD) age at interview was 43.36 (11.87) years. Ultrarare constrained variants (n = 400) were associated with lower current cognition scores (β = −0.18; SE = 0.07; P = .005). In the univariable analysis, premorbid IQ was associated with URCVs (β = −0.12; SE = 0.05; P = .02) and partly attenuated the association with current cognition (β = −0.09; SE = 0.05; P = .08). Multivariable analysis showed that measured genetic factors combined accounted for 6.2% of variance in current cognition, 10.3% of variance in premorbid IQ, and supported outcomes of URCVs associated with current cognition independent of premorbid IQ (β = −0.10; SE = 0.05; P = .03). The findings of this study suggest that URCVs contribute to variance in cognitive function in schizophrenia, with partly independent associations before and after onset of the disorder. Although the estimated effect sizes were small, future studies may show that the effect sizes will be greater with better annotation of pathogenic variants. Genomic data may contribute to identifying those at particularly high risk of cognitive impairment in whom early remedial or preventive measures can be implemented. This genetic association study assesses whether rare coding variants are associated with current cognitive function in patients with schizophrenia.
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DOI：
10.1093/bioinformatics/btu848
发表时间：
2015-05-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Euesden J;Lewis CM;O'Reilly PF
通讯作者：
O'Reilly PF
DOI：
10.1192/bjp.bp.113.131052
发表时间：
2014-02
期刊：
The British journal of psychiatry : the journal of mental science
影响因子：
--
作者：
Rees E;Walters JT;Georgieva L;Isles AR;Chambert KD;Richards AL;Mahoney-Davies G;Legge SE;Moran JL;McCarroll SA;O'Donovan MC;Owen MJ;Kirov G
通讯作者：
Kirov G
影响因子：
11
作者：
Lencz, T.;Knowles, E.;Davies, G.;Guha, S.;Liewald, D. C.;Starr, J. M.;Djurovic, S.;Melle, I.;Sundet, K.;Christoforou, A.;Reinvang, I.;Mukherjee, S.;DeRosse, Pamela;Lundervold, A.;Steen, V. M.;John, M.;Espeseth, T.;Raikkonen, K.;Widen, E.;Palotie, A.;Eriksson, J. G.;Giegling, I.;Konte, B.;Ikeda, M.;Roussos, P.;Giakoumaki, S.;Burdick, K. E.;Payton, A.;Ollier, W.;Horan, M.;Donohoe, G.;Morris, D.;Corvin, A.;Gill, M.;Pendleton, N.;Iwata, N.;Darvasi, A.;Bitsios, P.;Rujescu, D.;Lahti, J.;Hellard, S. L.;Keller, M. C.;Andreassen, O. A.;Deary, I. J.;Glahn, D. C.;Malhotra, A. K.
通讯作者：
Malhotra, A. K.
影响因子：
25.8
作者：
Mollon, Josephine;David, Anthony S.;Reichenberg, Abraham
通讯作者：
Reichenberg, Abraham
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G