Montalbano Simone, Krebs Morten Dybdahl, Rosengren Anders, Vaez Morteza, Hellberg Kajsa-Lotta Georgii, Mortensen Preben B, Børglum Anders D, Geschwind Daniel H, Raznahan Armin, Thompson Wesley K, Helenius Dorte, Werge Thomas, Ingason Andrés
Institute of Biological Psychiatry, Mental Health Services, Copenhagen University Hospital, Roskilde, Denmark.
The Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Copenhagen and Aarhus, Denmark.
NPJ Genom Med. 2024 Dec 19;9(1):67. doi: 10.1038/s41525-024-00450-8.
The NRXN1 locus is a hotspot for non-recurrent copy number variants and exon-disrupting NRXN1 deletions have been associated with increased risk of neurodevelopmental disorders in case-control studies. However, corresponding population-based estimates of prevalence and disease-associated risk are currently lacking. Also, most studies have not differentiated between deletions affecting exons of different NRXN1 splice variants nor considered intronic deletions. We used the iPSYCH2015 case-cohort sample to obtain unbiased estimates of the prevalence of NRXN1 deletions and their associated risk of autism, schizophrenia, depression, and ADHD. Most exon-disrupting deletions affected exons specific to the alpha isoform, and almost half of the non-exonic deletions represented a previously reported segregating founder deletion. Carriage of exon-disrupting NRXN1 deletions was associated with a threefold and twofold increased risk of autism and ADHD, respectively, whereas no significantly increased risk of depression or schizophrenia was observed. Our results highlight the importance of using population-based samples in genetic association studies.
NRXN1基因座是非复发性拷贝数变异的热点区域，在病例对照研究中，外显子破坏型NRXN1缺失与神经发育障碍风险增加有关。然而，目前缺乏基于人群的患病率和疾病相关风险的估计。此外，大多数研究没有区分影响不同NRXN1剪接变体的外显子的缺失，也没有考虑内含子缺失。我们使用iPSYCH2015病例队列样本来获得NRXN1缺失患病率及其与自闭症、精神分裂症、抑郁症和注意力缺陷多动障碍相关风险的无偏估计。大多数外显子破坏型缺失影响α异构体特有的外显子，并且几乎一半的非外显子缺失代表先前报道的分离的奠基者缺失。外显子破坏型NRXN1缺失携带者患自闭症和注意力缺陷多动障碍的风险分别增加了三倍和两倍，而未观察到抑郁症或精神分裂症风险显著增加。我们的结果强调了在基因关联研究中使用基于人群的样本的重要性。
