DESCRIPTION:
Bonferroni-significant results (p<2.63E-06) of gene-based association analyses (MAGMA) for TUD-EUR. We conducted independent GWAS of TUD cases and controls in individuals of European (EUR) ancestry across four U.S. biobanks (PsycheMERGE sites (BioVU, MGBB, PMBB, and MVP)) and performed a GWAS meta-analysis. We defined cases as patients who received at least two TUD ICD-9 or −10 codes (corresponding to the phecode definition) in their medical records, and controls as patients who had no TUD diagnosis codes. TUD-EUR included 11,422,241 imputed SNPs in a cohort of 163,734 TUD cases and 331,271 controls, which is 8.5 times larger than the total sample size of previous nicotine dependence GWAS. Genome-wide significant (GWS) loci were defined as those with p<5.00E-08 with LD r2>0.1, within a 1MB window, based on the structure of the Haplotype Reference Consortium (HRC) ancestry-appropriate reference panel. To identify TUD risk loci and lead SNPs, we performed LD clumping in FUMA using a range of 3 Mb, r2 >0.1, and the respective ancestry 1000 Genome reference panel. Genomic risk loci that were located <1Mb apart were incorporated into a single locus. For loci that harbored multiple variants, we used conditional & joint association analysis using GWAS summary statistics (COJO) in Genome-wide Complex Trait Analysis (GCTA) software to define independent variants by conditioning them on the most significant variant within each locus. Following conditioning, significant variants (p<5.00E-08) were considered independent. To further our biological interpretation of the TUD-EUR GWAS results and prioritize potential candidate genes and proteins, we performed multiple in silico downstream analyses. We conducted gene-based analyses via MAGMA v1.0841, which; Supplementary Table 15). SNPs were mapped to 19,532 protein-coding genes from Ensembl (build 85). We applied a Bonferroni correction based on the total number of genes tested (p<2.63E−06). Gene sets were obtained from Msigdb v7.0 (“Curated gene sets”, “GO terms”). The MAGMA analysis mapped SNP-level associations to 91 significant genes (p<2.63E-06), 20 (21.62%) of which replicated genes near or in GWS loci (e.g., CHRNA3, CHRNA4, KDM4A, DBH). P-values were 2-sided. The following geneset contains the results of MAGMA from the TUD-EUR analysis. From supplementary table 15.
LABEL:
MAGMA TUD-EUR_qvalue
SCORE TYPE:
Q-Value
THRESHOLD:
<= 0.5
GENES IN THRESHOLD:
85
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Genes in threshold: 85
| Uploaded As | Gene Symbol | Homology | Score | Priority | LinkOuts | Emphasis |
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