Identifying potential risk genes and pathways for neuropsychiatric and substance use disorders using intermediate molecular mediator information

Abstract

Neuropsychiatric and substance use disorders (NPSUDs) have a complex etiology that includes environmental and polygenic risk factors with significant cross-trait genetic correlations. Genome-wide association studies (GWAS) of NPSUDs yield numerous association signals. However, for most of these regions, we do not yet have a firm understanding of either the specific risk variants or the effects of these variants. Post-GWAS methods allow researchers to use GWAS summary statistics and molecular mediators (transcript, protein, and methylation abundances) infer the effect of these mediators on risk for disorders. One group of post-GWAS approaches is commonly referred to as transcriptome/proteome/methylome-wide association studies, which are abbreviated as T/P/MWAS (or collectively as XWAS). Since these approaches use biological mediators, the multiple testing burden is reduced to the number of genes (∼20,000) instead of millions of GWAS SNPs, which leads to increased signal detection. In this work, our aim is to uncover likely risk genes for NPSUDs by performing XWAS analyses in two tissues—blood and brain. First, to identify putative causal risk genes, we performed an XWAS using the Summary-data-based Mendelian randomization, which uses GWAS summary statistics, reference xQTL data, and a reference LD panel. Second, given the large comorbidities among NPSUDs and the shared cis-xQTLs between blood and the brain, we improved XWAS signal detection for underpowered analyses by performing joint concordance analyses between XWAS results i) across the two tissues and ii) across NPSUDs. All XWAS signals i) were adjusted for heterogeneity in dependent instruments (HEIDI) (non-causality) p-values and ii) used to test for pathway enrichment. The results suggest that there were widely shared gene/protein signals within the major histocompatibility complex region on chromosome 6 (BTN3A2 and C4A) and elsewhere in the genome (FURIN, NEK4, RERE, and ZDHHC5). The identification of putative molecular genes and pathways underlying risk may offer new targets for therapeutic development. Our study revealed an enrichment of XWAS signals in vitamin D and omega-3 gene sets. So, including vitamin D and omega-3 in treatment plans may have a modest but beneficial effect on patients with bipolar disorder.

Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling

“…Increased ANX risk was associated with increased expression of BTN3A2, NEK4 , and SLC12A5 and decreased expression of PSMG1 . To improve signal detection in brain transcriptome and methylome data, we used Primo (50) to jointly analyze blood and brain statistics (see Gedik et al (51)). We did not jointly analyze proteome data due to their rather low number of brain probes.…”

“…01, because a misalignment between the GWAS cohort population and the European LD reference panel used by SMR might yield very low P HEIDI . We previously arrived at this compromise between the two types of SMR p-values when applying this approach to many psychiatric disorders (51), e.g., the well-known SCZ C4A signal yielded a T-SMR P HEIDI = 5. 94 x 10 ™4 but a much lower P SMR .…”

Large-scale imputation models for multi-ancestry proteome-wide association analysis

“…Proteome-wide association studies (PWAS) have emerged as a promising approach to identify proteome-phenotype connections using genetically imputed proteomic models and GWAS summary statistics [17][18][19] . PWAS has been applied to understand the pathological mechanisms of multiple complex traits and diseases, including stroke 20 , Alzheimer's disease 19,21 , prostate cancer 22 , depression 23,24 , post-traumatic stress disorder (PTSD) 25,26 , neuropsychiatric and substance use disorders 27,28 , and multiple sclerosis 29 , aiding in the mapping of genetic causal pathways and identifying druggable targets.…”