Dataset Information

Gene-Based Analysis Reveals Sex-Specific Genetic Risk Factors of COPD.

ABSTRACT: Sex-specific differences have been noted among people with chronic obstructive pulmonary disease (COPD), but whether these differences are attributable to genetic variation is poorly understood. The availability of large biobanks with deeply phenotyped subjects such as the UK Biobank enables the investigation of sex-specific genetic associations that may provide new insights into COPD risk factors. We performed sex-stratified genome-wide association studies (GWAS) of COPD (male: 12,958 cases and 95,631 controls; female: 11,311 cases and 123,714 controls) and found that while most associations were shared between sexes, several regions had sex-specific contributions, including respiratory viral infection-related loci in/near C5orf56 and PELI1. Using the newly developed R package 'snpsettest', we performed gene-based association tests and identified gene-level sex-specific associations, including C5orf56 on 5q31.1, CFDP1/TMEM170A/CHST6 on 16q23.1 and ASTN2/TRIM32 on 9q33.1. Our results identified promising genes to pursue in functional studies to better understand sexual dimorphism in COPD.

SUBMITTER: Joo J

PROVIDER: S-EPMC8861659 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Gene-Based Analysis Reveals Sex-Specific Genetic Risk Factors of COPD.

Joo Jaehyun J Himes Blanca B

AMIA ... Annual Symposium proceedings. AMIA Symposium 20210101

Sex-specific differences have been noted among people with chronic obstructive pulmonary disease (COPD), but whether these differences are attributable to genetic variation is poorly understood. The availability of large biobanks with deeply phenotyped subjects such as the UK Biobank enables the investigation of sex-specific genetic associations that may provide new insights into COPD risk factors. We performed sex-stratified genome-wide association studies (GWAS) of COPD (male: 12,958 cases and ...[more]

PMID: 35308900

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Project description:ObjectivesBehçet's disease tends to be more severe in men than women. This study was undertaken to investigate sex-specific genetic effects in Behçet's disease.MethodsA total of 1762 male and 1216 female patients with Behçet's disease from six diverse populations were studied, with the majority of patients of Turkish origin. Genotyping was performed using an Infinium ImmunoArray-24 BeadChip, or extracted from available genotyping data. Following imputation and extensive quality control measures, genome-wide association analysis was performed comparing male to female patients in the Turkish cohort, followed by a meta-analysis of significant results in all six populations. In addition, a weighted genetic risk score for Behçet's disease was calculated and compared between male and female patients.ResultsGenetic association analysis comparing male to female patients with Behçet's disease from Turkey revealed an association with male sex in HLA-B/MICA within the HLA region with a GWAS level of significance (rs2848712, OR = 1.46, P = 1.22 × 10-8). Meta-analysis of the effect in rs2848712 across six populations confirmed these results. Genetic risk score for Behçet's disease was significantly higher in male compared to female patients from Turkey. Higher genetic risk for Behçet's disease was observed in male patients in HLA-B/MICA (rs116799036, OR = 1.45, P = 1.95 × 10-8), HLA-C (rs12525170, OR = 1.46, P = 5.66 × 10-7), and KLRC4 (rs2617170, OR = 1.20, P = 0.019). In contrast, IFNGR1 (rs4896243, OR = 0.86, P = 0.011) was shown to confer higher genetic risk in female patients.ConclusionsMale patients with Behçet's disease are characterized by higher genetic risk compared to female patients. This genetic difference, primarily derived from our Turkish cohort, is largely explained by risk within the HLA region. These data suggest that genetic factors might contribute to differences in disease presentation between men and women with Behçet's disease.

Project description:Parkinson's disease is an age-related neurodegenerative disorder with a higher incidence in males than females. The causes for this sex difference are unknown. Genome-wide association studies (GWAS) have identified 90 Parkinson's disease risk loci, but the genetic studies have not found sex-specific differences in allele frequency on autosomal chromosomes or sex chromosomes. Genetic variants, however, could exert sex-specific effects on gene function and regulation of gene expression. To identify genetic loci that might have sex-specific effects, we studied pleiotropy between Parkinson's disease and sex-specific traits. Summary statistics from GWASs were acquired from large-scale consortia for Parkinson's disease (n cases = 13 708; n controls = 95 282), age at menarche (n = 368 888 females) and age at menopause (n = 69 360 females). We applied the conditional/conjunctional false discovery rate (FDR) method to identify shared loci between Parkinson's disease and these sex-specific traits. Next, we investigated sex-specific gene expression differences in the superior frontal cortex of both neuropathologically healthy individuals and Parkinson's disease patients (n cases = 61; n controls = 23). To provide biological insights to the genetic pleiotropy, we performed sex-specific expression quantitative trait locus (eQTL) analysis and sex-specific age-related differential expression analysis for genes mapped to Parkinson's disease risk loci. Through conditional/conjunctional FDR analysis we found 11 loci shared between Parkinson's disease and the sex-specific traits age at menarche and age at menopause. Gene-set and pathway analysis of the genes mapped to these loci highlighted the importance of the immune response in determining an increased disease incidence in the male population. Moreover, we highlighted a total of nine genes whose expression or age-related expression in the human brain is influenced by genetic variants in a sex-specific manner. With these analyses we demonstrated that the lack of clear sex-specific differences in allele frequencies for Parkinson's disease loci does not exclude a genetic contribution to differences in disease incidence. Moreover, further studies are needed to elucidate the role that the candidate genes identified here could have in determining a higher incidence of Parkinson's disease in the male population.

Dataset Information

Gene-Based Analysis Reveals Sex-Specific Genetic Risk Factors of COPD.

Publications

Gene-Based Analysis Reveals Sex-Specific Genetic Risk Factors of COPD.

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