SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

IF 4.7 2区医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2023-09-28 DOI:10.1038/s41525-023-00370-z

Delnaz Roshandel, Eric J Sanders, Amy Shakeshaft, Naim Panjwani, Fan Lin, Amber Collingwood, Anna Hall, Katherine Keenan, Celine Deneubourg, Filippo Mirabella, Simon Topp, Jana Zarubova, Rhys H Thomas, Inga Talvik, Marte Syvertsen, Pasquale Striano, Anna B Smith, Kaja K Selmer, Guido Rubboli, Alessandro Orsini, Ching Ching Ng, Rikke S Møller, Kheng Seang Lim, Khalid Hamandi, David A Greenberg, Joanna Gesche, Elena Gardella, Choong Yi Fong, Christoph P Beier, Danielle M Andrade, Heinz Jungbluth, Mark P Richardson, Annalisa Pastore, Manolis Fanto, Deb K Pal, Lisa J Strug

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Abstract

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10^-9) and 10p11.21 (P = 3.6 × 10^-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10^-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10^-3) and increased seizure-like events (P = 6.8 × 10^-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10^-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

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SLCO5A1和突触组装基因对青少年肌阵挛性癫痫的冲动性有贡献。

冲动性升高是注意力缺陷多动障碍（ADHD）、双相情感障碍和青少年肌阵挛性癫痫（JME）的关键组成部分。我们对JME（n = 381）。使用果蝇模型对结果进行功能表征。我们在8q13.3发现了全基因组相关的SNPs（P = 7.5 × 10-9）和10p111.21（P = 3.6 × 10-8）。8q13.3基因座与大脑皮层SLCO5A1表达数量性状基因座共定位（P = 9.5 × 10-3）。SLCO5A1编码有机阴离子转运蛋白并上调突触组装/组织基因。通路分析显示突触前膜组装基因富集12.7倍（P = 0.0005）和14.3倍富集突触前组织基因（P = 0.0005），包括NLGN1和PTPRD。RNAi敲低与SLCO5A1同源性最高的果蝇多肽Oatp30B，会导致过度反应性休克行为（P = 8.7 × 10-3）和癫痫样事件增加（P = 6.8 × 10-7）。多动症的多基因风险评分与JME中的冲动性评分存在遗传相关性（P = 1.60 × 10-3）。SLCO5A1功能丧失代表了冲动和癫痫发作机制。突触组装基因可能为健康和疾病冲动的病因提供信息。

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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.