Interrogating Associations Between Polygenic Liabilities and Electroconvulsive Therapy Effectiveness

Abstract

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Independent Replication and Drug-specificity of an Antidepressant Response Polygenic Risk Score

“…Genotype data for 881 MDD participants was generated on an Affymetrix Direct-to-Consumer (DTC) array containing 497,962 single nucleotide polymorphisms (SNPs). Quality control procedures were performed using PLINK v1.9 [15] using widely accepted, rigorous and published quality control (QC) steps [11] (Supplementary Methods and Supplementary Table 3). In total, 520 European ancestry individuals and 382,258 SNPs passed these QC steps.…”

“…We used recent GWASs of AR [7] that employed two levels of outcomes: remission (PRS-AR Rem: remitters as cases and non-remitters as controls) and percentage improvement (PRS-AR Per ) for PRS calculations using standardized and published methods (Supplementary Methods) [11]. In brief, we constructed PRSs based on effect alleles weighted by effect estimate size, using PRSice2 [17] for 13 GWAS P-value thresholds (Pt): 5×10 −8 , 5×10 −7 , 5×10 −6 , 5×10 −5 , 5×10 −4 , 5×10 −3 , 0.05, 0.1, 0.2, 0.3, 0.4, 0.5 and 1.…”

“…The PRS-AR was generated using a meta-GWAS of AR to various antidepressants from multiple cohorts (>80% of patients treated with citalopram/escitalopram). In another set-up, we recently reported that high PRS-SCZ, but not PRS-AR, is associated with better response to ECT in MDD[11], suggesting PRS scores could have utility as stratification markers.…”

Multi‐polygenic scores in psychiatry: From disorder specific to transdiagnostic perspectives

“…Building upon the GWAS knowledge base, genetic sharing among psychiatric disorders has been evaluated, which revealed substantial genetic overlap at the genomic level (The Brainstorm Consortium et al, 2018) from which over a hundred genetic variants exerting pleiotropic effects on more than one disorder could be identified (Grotzinger et al, 2022; Lee et al, 2019). The identification of the polygenic architecture and effect sizes carried by individual single nucleotide polymorphisms (SNPs) enables researchers to quantify the combined genetic susceptibility to disorders in the form of polygenic risk scores (PRSs), whose usefulness has been shown in risk prediction for common diseases (Khera et al, 2018) and treatment outcome prediction (Luykx et al, 2022), in identifying cross‐disorder associations (Cross‐Disorder Group of the Psychiatric Genomics Consortium, 2013), but also in investigating complex traits that are relevant to multiple disorders (Bralten et al, 2021). However, the relations of PRSs for different psychiatric disorders with transdiagnostic traits have rarely been investigated in clinically rather typical, highly comorbid cohorts.…”

Multi-polygenic scores in psychiatry: from disorder-specific to transdiagnostic perspectives

“…Building upon the GWAS knowledge base, genetic sharing among psychiatric disorders has been evaluated, which revealed substantial genetic overlap at the genomic level [18] from which over a hundred genetic variants exerting pleiotropic effects on more than one disorders could be identified [19,20] . The identification of the polygenic architecture and effect sizes carried by individual single nucleotide polymorphisms (SNPs) enables researchers to quantify the combined genetic susceptibility to disorders in the form of polygenic risk scores (PRSs), whose usefulness has been shown in risk prediction for common diseases [21] and treatment outcome prediction [22] , in identifying cross-disorder associations [23] , but also in investigating complex traits that are relevant to multiple disorders [24] . However, the relations of PRS for different psychiatric disorders with transdiagnostic traits have rarely been investigated in clinically rather typical, highly comorbid cohorts.…”