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Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank.

ABSTRACT: Age-related hearing impairment (ARHI) is very common in older adults and has major impact on quality of life. The heritability of ARHI has been estimated to be around 50%. The present study aimed to estimate heritability and environmental contributions to liability of ARHI and the extent to which a polygenic risk score (PRS) derived from a recent genome-wide association study of questionnaire items regarding hearing loss using the UK Biobank is predictive of hearing loss in other samples. We examined (1) a sample from TwinsUK who have had hearing ability measured by pure-tone audiogram and the speech-to-noise ratio test as well as questionnaire measures that are comparable with the UK Biobank questionnaire items and (2) European and non-European samples from the UK Biobank which were not part of the original GWAS. Results indicated that the questionnaire items were over 50% heritable in TwinsUK and comparable with the objective hearing measures. In addition, we found very high genetic correlation (0.30-0.84) between the questionnaire responses and objective hearing measures in the TwinsUK sample. Finally, PRS computed from weighted UK Biobank GWAS results were predictive of both questionnaire and objective measures of hearing loss in the TwinsUK sample, as well as questionnaire-measured hearing loss in Europeans but not non-European subpopulations. These results demonstrate the utility of questionnaire-based methods in genetic association studies of hearing loss in adults and highlight the differences in genetic predisposition to ARHI by ethnic background.

SUBMITTER: Cherny SS

PROVIDER: S-EPMC7382483 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank.

Cherny Stacey S SS Livshits Gregory G Wells Helena R R HRR Freidin Maxim B MB Malkin Ida I Dawson Sally J SJ Williams Frances M K FMK

European journal of human genetics : EJHG 20200320 8

Age-related hearing impairment (ARHI) is very common in older adults and has major impact on quality of life. The heritability of ARHI has been estimated to be around 50%. The present study aimed to estimate heritability and environmental contributions to liability of ARHI and the extent to which a polygenic risk score (PRS) derived from a recent genome-wide association study of questionnaire items regarding hearing loss using the UK Biobank is predictive of hearing loss in other samples. We exa ...[more]

PMID: 32203203

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Project description:BackgroundCOVID-19 manifests with huge heterogeneity in susceptibility and severity outcomes. UK Black Asian and Minority Ethnic (BAME) groups have demonstrated disproportionate burdens. Some variability remains unexplained, suggesting potential genetic contribution. Polygenic Risk Scores (PRS) can determine genetic predisposition to disease based on Single Nucleotide Polymorphisms (SNPs) within the genome. COVID-19 PRS analyses within non-European samples are extremely limited. We applied a multi-ethnic PRS to a UK-based cohort to understand genetic contribution to COVID-19 variability.MethodsWe constructed two PRS for susceptibility and severity outcomes based on leading risk-variants from the COVID-19 Host Genetics Initiative. Scores were applied to 447,382 participants from the UK-Biobank. Associations with COVID-19 outcomes were assessed using binary logistic regression and discriminative power was validated using incremental area under receiver operating curve (ΔAUC). Variance explained was compared between ethnic groups via incremental pseudo-R2 (ΔR2).ResultsCompared to those at low genetic risk, those at high risk had a significantly greater risk of severe COVID-19 for White (odds ratio [OR] 1.57, 95% confidence interval [CI] 1.42-1.74), Asian (OR 2.88, 95% CI 1.63-5.09) and Black (OR 1.98, 95% CI 1.11-3.53) ethnic groups. Severity PRS performed best within Asian (ΔAUC 0.9%, ΔR2 0.98%) and Black (ΔAUC 0.6%, ΔR2 0.61%) cohorts. For susceptibility, higher genetic risk was significantly associated with COVID-19 infection risk for the White cohort (OR 1.31, 95% CI 1.26-1.36), but not for Black or Asian groups.ConclusionsSignificant associations between PRS and COVID-19 outcomes were elicited, establishing a genetic basis for variability in COVID-19. PRS showed utility in identifying high-risk individuals. The multi-ethnic approach allowed applicability of PRS to diverse populations, with the severity model performing well within Black and Asian cohorts. Further studies with larger sample sizes of non-White samples are required to increase statistical power and better assess impacts within BAME populations.

Project description:BackgroundChildhood maltreatment is common globally and impacts morbidity, mortality, and well-being. Our understanding of its impact is constrained by key substantive and methodological limitations of extant research, including understudied physical health outcomes and bias due to unmeasured confounding. We address these limitations through a large-scale outcome-wide triangulation study.MethodsWe performed two outcome-wide analyses (OWAs) in the UK Biobank. First, we examined the relationship between self-reported maltreatment exposure (number of maltreatment types, via Childhood Trauma Screener) and 414 outcomes in a sub-sample of 157,316 individuals using generalized linear models ("observational OWA"). Outcomes covered a broad range of health themes including health behaviors, cardiovascular disease, digestive health, socioeconomic status, and pain. Second, we examined the relationship between a polygenic risk score for maltreatment and 298 outcomes in a non-overlapping sample of 243,006 individuals ("genetic OWA"). We triangulated results across OWAs based on differing sources of bias.ResultsOverall, 23.8% of the analytic sample for the observational OWA reported at least one maltreatment type. Of 298 outcomes examined in both OWAs, 25% were significant in both OWAs and concordant in the direction of association. Most of these were considered robust in the observational OWA according to sensitivity analyses and included outcomes such as marital separation (OR from observational OWA, ORo = 1.25 (95% CI: 1.21, 1.29); OR from genetic OWA, ORg = 1.06 (1.03, 1.08)), major diet changes due to illness (ORo = 1.27 (1.24, 1.29); ORg = 1.01 (1.00, 1.03)), certain intestinal diseases (ORo = 1.14 (1.10, 1.18); ORg = 1.03 (1.01, 1.06)), hearing difficulty with background noise (ORo = 1.11 (1.11, 1.12); ORg = 1.01 (1.00, 1.01)), knee arthrosis (ORo = 1.13 (1.09, 1.18); ORg = 1.03 (1.01, 1.05)), frequent sleeplessness (ORo = 1.21 (1.20, 1.23); ORg = 1.02 (1.01, 1.03)), and low household income (ORo = 1.28 (1.26, 1.31); ORg = 1.02 (1.01, 1.03)). Approximately 62% of results were significant in the observational OWA but not the genetic OWA, including numerous cardiovascular outcomes. Only 6 outcomes were significant in the genetic OWA and null in the observational OWA; these included diastolic blood pressure and glaucoma. No outcomes were statistically significant in opposite directions in the two analyses, and 11% were not significant in either OWA.ConclusionsOur findings underscore the far-reaching negative effects of childhood maltreatment in later life and the utility of an outcome-wide triangulation design with sensitivity analyses for improving causal inference.

Project description:Background: Monogenic familial hypercholesterolaemia (FH) is an autosomal dominant disorder characterised by elevated low-density lipoprotein cholesterol (LDL-C) concentrations due to monogenic mutations in LDLR, APOB, PCSK9, and APOE. Some mutation-negative patients have a polygenic cause for elevated LDL-C due to a burden of common LDL-C-raising alleles, as demonstrated in people of White British (WB) ancestry using a 12-single nucleotide polymorphism (SNP) score. This score has yet to be evaluated in people of South Asian (SA), and Black and Caribbean (BC) ethnicities. Objectives: 1) Compare the LDL-C and 12-SNP score distributions across the three major ethnic groups in the United Kingdom: WB, SA, and BC individuals; 2) compare the association of the 12-SNP score with LDL-C in these groups; 3) evaluate ethnicity-specific and WB 12-SNP score decile cut-off values, applied to SA and BC ethnicities, in predicting LDL-C concentrations and hypercholesterolaemia (LDL-C>4.9 mmol/L). Methods: The United Kingdom Biobank cohort was used to analyse the LDL-C (adjusted for statin use) and 12-SNP score distributions in self-reported WB (n = 353,166), SA (n = 7,016), and BC (n = 7,082) participants. To evaluate WB and ethnicity-specific 12-SNP score deciles, the total dataset was split 50:50 into a training and testing dataset. Regression analyses (logistic and linear) were used to analyse hypercholesterolaemia (LDL-C>4.9 mmol/L) and LDL-C. Findings: The mean (±SD) measured LDL-C differed significantly between the ethnic groups and was highest in WB [3.73 (±0.85) mmol/L], followed by SA [3.57 (±0.86) mmol/L, p < 2.2 × 10-16], and BC [3.42 (±0.90) mmol/L] participants (p < 2.2 × 10-16). There were significant differences in the mean (±SD) 12-SNP score between WB [0.90 (±0.23)] and BC [0.72 (±0.25), p < 2.2 × 10-16], and WB and SA participants [0.86 (±0.19), p < 2.2 × 10-16]. In all three ethnic groups the 12-SNP score was associated with measured LDL-C [R 2 (95% CI): WB = 0.067 (0.065-0.069), BC = 0.080 (0.063-0.097), SA = 0.027 (0.016-0.038)]. The odds ratio and the area under the curve for hypercholesterolaemia were not statistically different when applying ethnicity-specific or WB deciles in all ethnic groups. Interpretation: We provide information on the differences in LDL-C and the 12-SNP score distributions in self-reported WB, SA, and BC individuals of the United Kingdom Biobank. We report the association between the 12-SNP score and LDL-C in these ethnic groups. We evaluate the performance of ethnicity-specific and WB 12-SNP score deciles in predicting LDL-C and hypercholesterolaemia.

Dataset Information

Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank.

Publications

Self-reported hearing loss questions provide a good measure for genetic studies: a polygenic risk score analysis from UK Biobank.

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