Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect
Genome-Wide Association Study Detected Novel Susceptibility Genes for Schizophrenia and Shared Trans-Populations/Diseases Genetic Effect
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DOI：
10.1093/schbul/sby140
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发表时间：
2019-07-01
影响因子：
6.6
通讯作者：
Iwata, Nakao
中科院分区：
文献类型：
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作者：
Ikeda, Masashi;Takahashi, Atsushi;Iwata, Nakao
全基因组关联研究（GWAS）已经确定了超过100万个精神分裂症（SCZ）的易感位点，并表明精神分裂症是一种由众多遗传变异决定的多基因疾病，但效应量较小。我们在日本人群中进行了一项GWAS，（a）以检测新的精神分裂症易感基因，（b）检验精神分裂症在（东亚和欧洲）人群之间以及/或者跨疾病（东亚地区内以及东亚和欧洲之间的精神分裂症、双相情感障碍[BD]和重性抑郁障碍[MDD]，跨疾病/人群）的共同遗传风险。在发现阶段的GWAS受试者（日本精神分裂症GWAS：1940例精神分裂症病例和7408例对照）和复制数据集（4071例精神分裂症病例和54479例对照）中，两者都由日本人群组成，确定了3个新的精神分裂症易感位点：SPHKAP（最佳P值 = 4.1×10⁻¹⁰）、SLC38A3（最佳P值 = 5.7×10⁻¹⁰）和CABP1 - ACADS（最佳P值 = 9.8×10⁻⁹）。随后在我们的样本与精神疾病GWAS联盟（PGC；欧洲样本）以及另一项研究的样本之间进行的荟萃分析检测到了另外12个易感位点。多基因风险评分（PRS）预测揭示了精神分裂症在人群之间（最佳P值 = 4.0×10⁻¹¹）以及在日本人群中精神分裂症和双相情感障碍之间（P值约为10⁻⁴⁰）的共同遗传风险；然而，注意到日本精神分裂症GWAS与PGC - BD或MDD在人群内/人群间的解释方差较低。遗传相关性分析支持了PRS结果；日本精神分裂症与PGC - 精神分裂症之间的遗传相关性为ρ = 0.58，而在跨疾病（日本精神分裂症与日本双相情感障碍/东亚 - MDD，r(g) = 0.56/0.29）或跨疾病/人群（日本精神分裂症与PGC - BD/MDD，ρ = 0.38/0.12）之间观察到相似/较低的相关性。总之，（a）15个新的位点可能是精神分裂症的易感基因，（b）精神分裂症的“风险”效应甚至在人群之间与其他精神疾病是共享的。
Genome-wide association studies (GWASs) have identified >1(M) susceptibility loci for schizophrenia (SCZ) and demonstrated that SCZ is a polygenic disorder determined by numerous genetic variants but with small effect size. We conducted a GWAS in the Japanese (JPN) population (a) to detect novel SCZ-susceptibility genes and (b) to examine the shared genetic risk of SCZ across (East Asian WAS' and European [EUR]) populations and/or that of trans-diseases (SCZ, bipolar disorder [BD], and major depressive disorder [MDD] within EAS and between EAS and EUR (transdiseases/populations). Among the discovery GWAS subjects (JPN-SCZ GWAS: 1940 SCZ cases and 7408 controls) and replication dataset (4071 SCZ cases and 54479 controls), both comprising JPN populations, 3 novel susceptibility loci for SCZ were identified: SPHKAP (P-best = 4.1 x 10(-10)), SLC38A3 (P-best = 5.7 x 10(-10)), and CABP1-ACADS (P-best = 9.8 x 10(-9)). Subsequent meta-analysis between our samples and those of the Psychiatric GWAS Consortium (PGC; EUR samples) and another study detected 12 additional susceptibility loci. Polygenic risk score (PRS) prediction revealed a shared genetic risk of SCZ across populations (P-best = 4.0 x 10(-11)) and between SCZ and BD in the JPN population (P similar to 10(-40)); however, a lower variance-explained was noted between JPN-SCZ GWAS and PGC-BD or MDD within/across populations. Genetic correlation analysis supported the PRS results; the genetic correlation between JPN-SCZ and PGC-SCZ was rho = 0.58, whereas a similar/lower correlation was observed between the trans-diseases (JPN-SCZ vs JPN-BD/EAS-MDD, r(g) = 0.56/0.29) or trans-diseases/populations (JPN-SCZ vs PGC-BD/MDD, rho = 0.38/0.12). In conclusion, (a) Fifteen novel loci are possible susceptibility genes for SCZ and (b) SCZ "risk" effect is shared with other psychiatric disorders even across populations.