Department of Genetics, University of Delhi South Campus, New Delhi, India.
Department of Psychiatry, PGIMER-Dr. RML Hospital, New Delhi, India.
Schizophr Bull. 2019 Jan 1;45(1):256-263. doi: 10.1093/schbul/sbx196.
Candidate gene and genome-wide association study based common risk variant identification is being complemented by whole exome sequencing (WES)/whole genome sequencing based rare variant discovery in elucidation of genetic landscape of schizophrenia (SZ), a common neuropsychiatric disorder. WES findings of de novo mutations in case-parent trios have further implied genetic etiology, but do not explain the high genetic risk in general populations. Conversely, WES in multiplex families may be an insightful strategy for the identification of highly penetrant rare variants in SZ and possibly enhance our understanding of disease biology. In this study, we analyzed a 5-generation Indian family with multiple members affected with SZ by WES. We identified a rare heterozygous missense variant (NM_003255: c.506C>T; p.Pro169Leu; MAF = 0.0001) in Tissue Inhibitor of Metalloproteinase 2 (TIMP2, 17q25.3) segregating with all 6 affected individuals but not with unaffected members. Linkage analysis indicated a maximum logarithm of the odds score of 1.8, θ = 0 at this locus. The variant was predicted to be damaging by various in silico tools and also disrupt the structural integrity by molecular dynamics simulations. WES based screening of an independent SZ cohort (n = 370) identified 4 additional rare missense variants (p.Leu20Met, p.Ala26Ser, p.Lys48Arg and p. Ile217Leu) and a splice variant rs540397728 (NM_003255:c.232-5T>C), also predicted to be damaging, increasing the likelihood of contribution of this gene to SZ risk. Extensive biochemical and knockout mouse studies suggesting involvement of TIMP2 in neurodevelopmental and behavioral deficits, together with genetic evidence for TIMP2 conferring SZ risk from this study may have possible implications for new therapeutics.
基于候选基因和全基因组关联研究的常见风险变异识别，正在通过外显子组测序（WES）/全基因组测序的罕见变异发现来阐明精神分裂症（SZ）的遗传图谱，SZ 是一种常见的神经精神疾病。病例-父母三体型中的新生突变的 WES 发现进一步暗示了遗传病因，但不能解释一般人群中的高遗传风险。相反，在多重家庭中进行 WES 可能是鉴定 SZ 中高外显率罕见变异的一种有见地的策略，并可能增强我们对疾病生物学的理解。在这项研究中，我们通过 WES 分析了一个有多个 SZ 患者的 5 代印度家族。我们在组织抑制剂金属蛋白酶 2（TIMP2，17q25.3）中发现了一个罕见的杂合错义变异（NM_003255：c.506C>T；p.Pro169Leu；MAF=0.0001），该变异与所有 6 名受影响个体共分离，但与未受影响个体不共分离。连锁分析表明，该位点的最大对数优势分数为 1.8，θ=0。该变异被各种计算机预测工具预测为有害，并且通过分子动力学模拟破坏了结构完整性。对独立 SZ 队列（n=370）的 WES 筛查确定了另外 4 个罕见的错义变异（p.Leu20Met、p.Ala26Ser、p.Lys48Arg 和 p.Ile217Leu）和一个剪接变异 rs540397728（NM_003255：c.232-5T>C），也被预测为有害，增加了该基因对 SZ 风险的贡献可能性。广泛的生化和 knockout 小鼠研究表明 TIMP2 参与神经发育和行为缺陷，以及本研究中 TIMP2 遗传证据表明 SZ 风险，这可能对新的治疗方法具有重要意义。
