Polygenic scores stratify neurodevelopmental copy number variant carrier cognitive outcomes in the UK Biobank.

IF 4.7 2区医学 Q1 GENETICS & HEREDITY

NPJ Genomic Medicine Pub Date : 2024-09-28 DOI:10.1038/s41525-024-00426-8

Thomas J Dinneen, Fiana Ní Ghrálaigh, Cathal Ormond, Elizabeth A Heron, George Kirov, Lorna M Lopez, Louise Gallagher

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Abstract

Rare copy-number variants associated with neurodevelopmental conditions (ND-CNVs) exhibit variable expressivity of clinical, physical, behavioural outcomes. Findings from clinically ascertained cohorts suggest this variability may be partly due to additional genetic variation. Here, we assessed the impact of polygenic scores (PGS) and rare variants on ND-CNV carrier fluid intelligence (FI) scores in the UK Biobank. Greater PGS for cognition (PS_Cog) and educational attainment (PS_EA) is associated with increased FI scores in all ND-CNVs (n = 1317), 15q11.2 del. (n = 543), and 16p13.11 dup. carriers (n = 275). No association of rare variants associated with intellectual disability, autism, or putatively loss-of-function, brain-expressed genes was found. Positive predictive values in the first deciles of PS_cog and PS_EA showed a two- to five-fold increase in the rate of low FI scores compared to baseline rates. These findings demonstrate that PGS can stratify ND-CNV carrier cognitive outcomes in a population-based cohort.

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英国生物库中神经发育拷贝数变异携带者认知结果的多基因分层。

与神经发育状况相关的罕见拷贝数变异（ND-CNVs）在临床、身体和行为结果上表现出不同的表达性。临床确定队列的研究结果表明，这种可变性可能部分是由于额外的遗传变异造成的。在此，我们评估了英国生物库中多基因评分（PGS）和罕见变异对 ND-CNV 携带者流体智力（FI）评分的影响。在所有 ND-CNVs（n = 1317）、15q11.2 del.（n = 543）和 16p13.11 dup.携带者（n = 275）中，认知（PSCog）和教育程度（PSEA）的 PGS 越高，流体智力（FI）得分越高。没有发现与智力障碍、自闭症或功能缺失、脑表达基因相关的罕见变异。PScog和PSEA前十分位数的阳性预测值显示，与基线比率相比，FI低分率增加了2至5倍。这些研究结果表明，PGS 可以在基于人群的队列中对 ND-CNV 携带者的认知结果进行分层。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology

CiteScore

9.40

自引率

1.90%

发文量

审稿时长

17 weeks

期刊介绍： npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.