Table 1_Phenome-wide association studies between SERINC2 and neuropsychiatric disorders.xlsx

ObjectivesSERINC2 has been associated with alcoholism, bipolar disorder and autism, but the comparability and specificity issues of the findings remain unaddressed. The present study aimed to comprehensively analyze various neuropsychiatric disorders pinpoint the most reliable conditions predisposed by SERINC2.
MethodsA total of 2,187 imputed SNPs across SERINC2 were examined in 1,167,439 subjects from 72 independent cohorts with 18 different neuropsychiatric disorders. SNP-disease associations were tested and then meta-analyzed, followed by FDR correction, to identify significant disease-risk SNPs. Finally, functional studies on the differential SERINC2 mRNA expression in brains and the potential regulatory effects of disease-risk alleles on SERINC2 mRNA expression, gray matter volumes (GMVs) of subcortical structures, cortical surface area (SA) and average thickness (TH) were conducted.
ResultsIn European descent, alcoholism was most significantly associated with SERINC2 variants (245 SNPs with 5.5×10-8≤p ≤ 0.049 and 4.9×10-5≤q ≤ 0.034) that were largely shared across cocaine dependence, marijuana dependence, nicotine dependence, polysubstance dependence, schizophrenia, OCD, and autism (8.2×10-8≤p ≤ 0.050 and 1.9×10-5≤q ≤ 0.049); in Chinese population, bipolar disorder was also significantly associated with SERINC2 variants (10 SNPs: 1.3×10-4≤p ≤ 4.7×10-4 and 0.025≤q ≤ 0.031). Furthermore, the disease-risk alleles had highly similar regulatory effects on mRNA expression (8.1×10-7≤p ≤ 0.046), subcortical GMVs (7.0×10-4≤p ≤ 0.048) and cortical TH and SA (1.3×10-3≤p ≤ 0.050) in brains across alcoholism, schizophrenia, OCD and autism. The bipolar disorder-risk alleles had these regulatory effects but with different effect patterns. Finally, SERINC2 mRNA was differentially expressed in several brain regions between alcoholism or schizophrenia and controls.
ConclusionSERINC2 is primarily linked to substance use disorders, schizophrenia, OCD, autism and bipolar disorder, not only statistically but also biologically.

研究目的：既往研究表明，SERINC2与酒精成瘾、双相情感障碍及孤独症相关，但现有研究结果的可比性与特异性问题尚未得到解决。本研究旨在全面分析各类神经精神疾病，精准定位SERINC2所介导的最可靠易感疾病表型。
研究方法：本研究纳入来自72个独立队列的1167439名受试者，覆盖18种不同的神经精神疾病，对SERINC2基因区域内的2187个经基因型填充的单核苷酸多态性（Single Nucleotide Polymorphism，SNP）进行检测。首先开展SNP-疾病关联分析，随后进行荟萃分析并结合错误发现率（False Discovery Rate，FDR）校正，以鉴定具有显著疾病风险的SNP。最后，针对SERINC2信使RNA（messenger RNA，mRNA）在大脑中的差异表达情况，以及疾病风险等位基因对SERINC2 mRNA表达、皮层下结构灰质体积（Gray Matter Volumes，GMVs）、皮层表面积（Cortical Surface Area，SA）及平均厚度（Average Thickness，TH）的潜在调控效应进行功能研究。
研究结果：在欧洲血统人群中，酒精成瘾与SERINC2变异体的关联最为显著（共245个SNP，其P值范围为5.5×10^-8至0.049，FDR校正后q值范围为4.9×10^-5至0.034），且该关联信号在可卡因依赖、大麻依赖、尼古丁依赖、多物质依赖、精神分裂症、强迫症（Obsessive-Compulsive Disorder，OCD）及孤独症中广泛共享（P值范围为8.2×10^-8至0.050，q值范围为1.9×10^-5至0.049）；在中国人群中，双相情感障碍同样与SERINC2变异体存在显著关联（共10个SNP，P值范围为1.3×10^-4至4.7×10^-4，q值范围为0.025至0.031）。进一步分析显示，疾病风险等位基因对酒精成瘾、精神分裂症、OCD及孤独症患者大脑内的mRNA表达（P值范围为8.1×10^-7至0.046）、皮层下灰质体积（P值范围为7.0×10^-4至0.048）以及皮层厚度与表面积（P值范围为1.3×10^-3至0.050）均具有高度相似的调控效应。双相情感障碍风险等位基因虽也具备此类调控效应，但作用模式存在差异。最终发现，在酒精成瘾或精神分裂症患者与健康对照的多个脑区中，SERINC2 mRNA的表达水平存在显著差异。
研究结论：SERINC2主要与物质使用障碍、精神分裂症、OCD、孤独症及双相情感障碍相关，该关联不仅具有统计学显著性，同时具备生物学合理性。