Fabbri C, Tansey K E, Perlis R H, Hauser J, Henigsberg N, Maier W, Mors O, Placentino A, Rietschel M, Souery D, Breen G, Curtis C, Sang-Hyuk L, Newhouse S, Patel H, Guipponi M, Perroud N, Bondolfi G, O'Donovan M, Lewis G, Biernacka J M, Weinshilboum R M, Farmer A, Aitchison K J, Craig I, McGuffin P, Uher R, Lewis C M
Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
Pharmacogenomics J. 2018 May 22;18(3):413-421. doi: 10.1038/tpj.2017.44. Epub 2017 Nov 21.
Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STARD) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STARD (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.
全基因组关联研究通常未能识别出与抗抑郁反应相关的多态性。可能的原因包括该研究试图通过外显子基因分型和密集填充来解决的遗传变异覆盖范围有限。在单核苷酸多态性（SNP）、基因和通路水平上对基于基因组的抑郁症治疗药物（GENDEP）和缓解抑郁症的序贯治疗替代方案（STARD）研究进行了荟萃分析。通过将外显子基因型添加到先前可用的全基因组数据中，并使用单倍型参考联盟面板进行填充，与先前的研究相比，遗传变异的覆盖范围有所增加。应用了标准质量控制。表型为抗抑郁治疗12周后的症状改善和缓解。在NEWMEDS联盟样本和药物基因组学研究网络抗抑郁药物药物基因组学研究（PGRN-AMPS）中对显著发现进行了重复验证。在GENDEP（n = 738）和STARD（n = 1409）中总共分析了7062950个SNP。rs116692768（P = 1.80e-08，ITGA9（整合素α9））和rs76191705（P = 2.59e-08，NRXN3（神经纤连蛋白3））与西酞普兰/艾司西酞普兰治疗期间的症状改善显著相关。在基因水平上，未发现一致的效应。在通路水平上，基因本体论（GO）术语GO: 0005694（染色体）和GO: 0044427（染色体部分）与改善相关（校正P分别为0.007和0.045）。rs116692768与症状改善之间的关联在PGRN-AMPS中得到重复验证（P = 0.047），而rs76191705未得到重复验证。这两个SNP在NEWMEDS中未得到重复验证。ITGA9编码神经营养因子的膜受体,NRXN3是一种参与突触分化的跨膜神经元粘附受体。尽管它们参与抗抑郁作用有合理的生物学原理，但重复验证并不完全。进一步的研究可能有助于阐明它们的作用。
