Dinneen Thomas J, Ní Ghrálaigh Fiana, Ormond Cathal, Heron Elizabeth A, Kirov George, Lopez Lorna M, Gallagher Louise
Trinity College Dublin, Department of Psychiatry, School of Medicine, Trinity Centre for Health Sciences, St. James' Hospital, Dublin 8, Ireland.
The Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, 686 Bay St., Toronto, ON, M5G 0A4, Canada.
NPJ Genom Med. 2024 Sep 28;9(1):43. doi: 10.1038/s41525-024-00426-8.
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) and educational attainment (PS) 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 and PS 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.
与神经发育疾病相关的罕见拷贝数变异（ND-CNVs）在临床、身体和行为结果方面表现出可变的表达性。来自临床确诊队列的研究结果表明，这种变异性可能部分归因于额外的基因变异。在此，我们在英国生物银行中评估了多基因评分（PGS）和罕见变异对ND-CNV携带者流体智力（FI）分数的影响。在所有ND-CNV携带者（n = 1317）、15q11.2缺失携带者（n = 543）和16p13.11重复携带者（n = 275）中，更高的认知多基因评分（PS）和教育程度多基因评分（PS）与更高的FI分数相关。未发现与智力残疾、自闭症或假定的功能丧失的脑表达基因相关的罕见变异之间存在关联。PS和PS前十分位数的阳性预测值显示，与基线率相比，低FI分数的发生率增加了两到五倍。这些发现表明，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。
