Janssen Research & Development, LLC, Titusville, NJ, USA.
23andMe, Inc., Sunnyvale, CA, USA.
Transl Psychiatry. 2020 Oct 26;10(1):360. doi: 10.1038/s41398-020-01035-6.
The "antidepressant efficacy" survey (AES) was deployed to > 50,000 23andMe, Inc. research participants to investigate the genetic basis of treatment-resistant depression (TRD) and non-treatment-resistant depression (NTRD). Genome-wide association studies (GWAS) were performed, including TRD vs. NTRD, selective serotonin reuptake inhibitor (SSRI) responders vs. non-responders, serotonin-norepinephrine reuptake inhibitor (SNRI) responders vs. non-responders, and norepinephrine-dopamine reuptake inhibitor responders vs. non-responders. Only the SSRI association reached the genome-wide significance threshold (p < 5 × 10): one genomic region in RNF219-AS1 (SNP rs4884091, p = 2.42 × 10, OR = 1.21); this association was also observed in the meta-analysis (13,130 responders vs. 6,610 non-responders) of AES and an earlier "antidepressant efficacy and side effects" survey (AESES) cohort. Meta-analysis for SNRI response phenotype derived from AES and AESES (4030 responders vs. 3049 non-responders) identified another genomic region (lead SNP rs4955665, p = 1.62 × 10, OR = 1.25) in an intronic region of MECOM passing the genome-wide significance threshold. Meta-analysis for the TRD phenotype (31,068 NTRD vs 5,714 TRD) identified one additional genomic region (lead SNP rs150245813, p = 8.07 × 10, OR = 0.80) in 10p11.1 passing the genome-wide significance threshold. A stronger association for rs150245813 was observed in current study (p = 7.35 × 10, OR = 0.79) than the previous study (p = 1.40 × 10, OR = 0.81), and for rs4955665, a stronger association in previous study (p = 1.21 × 10, OR = 1.27) than the current study (p = 2.64 × 10, OR = 1.21). In total, three novel loci associated with SSRI or SNRI (responders vs. non-responders), and NTRD vs TRD were identified; gene level association and gene set enrichment analyses implicate enrichment of genes involved in immune process.
“抗抑郁疗效”调查（AES）在 23andMe，Inc. 的超过 50000 名研究参与者中进行，以研究治疗抵抗性抑郁症（TRD）和非治疗抵抗性抑郁症（NTRD）的遗传基础。进行了全基因组关联研究（GWAS），包括 TRD 与 NTRD、选择性 5-羟色胺再摄取抑制剂（SSRI）应答者与非应答者、5-羟色胺-去甲肾上腺素再摄取抑制剂（SNRI）应答者与非应答者、以及去甲肾上腺素-多巴胺再摄取抑制剂应答者与非应答者。只有 SSRI 关联达到全基因组显著阈值（p < 5×10）：一个位于 RNF219-AS1 中的基因组区域（SNP rs4884091，p = 2.42×10，OR = 1.21）；该关联也在 AES 和早期“抗抑郁疗效和副作用”调查（AESES）队列的荟萃分析（13130 名应答者与 6610 名非应答者）中观察到。从 AES 和 AESES 中得出的 SNRI 反应表型的荟萃分析（4030 名应答者与 3049 名非应答者）确定了另一个基因组区域（主要 SNP rs4955665，p = 1.62×10，OR = 1.25）在 MECOM 的内含子区域，该区域通过了全基因组显著阈值。TRD 表型（31068 名 NTRD 与 5714 名 TRD）的荟萃分析确定了另一个基因组区域（主要 SNP rs150245813，p = 8.07×10，OR = 0.80）在 10p11.1 通过了全基因组显著阈值。rs150245813 的关联在本研究中更强（p = 7.35×10，OR = 0.79），而在先前的研究中更强（p = 1.40×10，OR = 0.81），对于 rs4955665，先前研究中的关联更强（p = 1.21×10，OR = 1.27），而本研究中的关联较弱（p = 2.64×10，OR = 1.21）。总共确定了三个与 SSRI 或 SNRI（应答者与非应答者）以及 NTRD 与 TRD 相关的新基因座；基因水平关联和基因集富集分析表明，与免疫过程相关的基因富集。
