Genome-wide haplotype-based association analysis of major depressive disorder in Generation Scotland and UK Biobank

Abstract

Genome-wide association studies using genotype data have had limited success in the identification of variants associated with major depressive disorder (MDD). Haplotype data provide an alternative method for detecting associations between variants in weak linkage disequilibrium with genotyped variants and a given trait of interest. A genome-wide haplotype association study for MDD was undertaken utilising a family-based population cohort, Generation Scotland: Scottish Family Health Study (n = 18,773), as a discovery cohort with UK Biobank used as a population-based replication cohort (n = 25,035). Fine mapping of haplotype boundaries was used to account for overlapping haplotypes potentially tagging the same causal variant. Within the discovery cohort, two haplotypes exceeded genome-wide significance (P < 5 × 10) for an association with MDD. One of these haplotypes was nominally significant in the replication cohort (P < 0.05) and was located in 6q21, a region which has been previously associated with bipolar disorder, a psychiatric disorder that is phenotypically and genetically correlated with MDD. Several haplotypes with P < 10 −7 in the discovery cohort were located within gene coding regions associated with diseases that are comorbid with MDD. Using such haplotypes to highlight regions for sequencing may lead to the identification of the underlying causal variants.

Genome-wide haplotype association study in imaging genetics using whole-brain sulcal openings of 16,304 UK Biobank subjects

“…Using Bonferroni correction for multiple testing is expected to be conservative in the presence of such dependencies. In this situation, Howard et al [29] proposed a correction using an estimation of the number of independent haplotypes, which would be less stringent than the Bonferroni correction.…”

Electronic Health Record and Genome-wide Genetic Data in Generation Scotland Participants

“…and prescription data (for history of antidepressants). This information has been used in haplotype association analyses of MDD 14 , stratification of MDD into genetic subgroups 15 and genome-wide meta-analyses of stratified depression. 16 Data science has great potential as a catalyst for improved mental health recognition, understanding, support and outcomes.…”

Retrospective analysis ofThe Two Sister Studyusing haplotype-based association testing to identify loci associated with early-onset breast cancer

“…Haplotype-based analysis has been used to gain insight in a wide array of complex disease models including mood disorders, multiple sclerosis, orofacial clefting, and cancer (13)(14)(15)(16)(17)(18). Moreover, haplotype-based analysis has been effectively applied to investigate age-of-onset in human disease although relatively few studies have specifically addressed EOBC (19)(20)(21)(22)(23).…”

“…Haplotypes, which consist of a series of sequentially ordered single nucleotide variants (SNVs), are a potentially more informative format for association testing than single markers and may have improved sensitivity and specificity for discovery ( 11, 12 ). Haplotype-based analysis has been used to gain insight in a wide array of complex disease models including mood disorders, multiple sclerosis, orofacial clefting, and cancer ( 13-18 ). Moreover, haplotype-based analysis has been effectively applied to investigate age-of-onset in human disease although relatively few studies have specifically addressed EOBC ( 19-23 ).…”