The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis.
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ABSTRACT:
SUBMITTER: Ivarsdottir EV
PROVIDER: S-EPMC8190123 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:This study aimed at contributing to the elucidation of the genetic basis of age-related hearing impairment (ARHI), a common multifactorial disease with an important genetic contribution as demonstrated by heritability studies. We conducted a genome-wide association study (GWAS) in the Finnish Saami, a small, ancient, genetically isolated population without evidence of demographic expansion. The choice of this study population was motivated by its anticipated higher extent of LD, potentially offering a substantial power advantage for association mapping. DNA samples and audiometric measurements were collected from 352 Finnish Saami individuals, aged between 50 and 75 years. To reduce the burden of multiple testing, we applied principal component (PC) analysis to the multivariate audiometric phenotype. The first three PCs captured 80% of the variation in hearing thresholds, while maintaining biologically important audiometric features. All subjects were genotyped with the Affymetrix 100 K chip. To account for multiple levels of relatedness among subjects, as well as for population stratification, association testing was performed using a mixed model. We summarised the top-ranking association signals for the three traits under study. The top-ranked SNP, rs457717 (P-value 3.55 x 10(-7)), was associated with PC3 and was localised in an intron of the IQ motif-containing GTPase-activating-like protein (IQGAP2). Intriguingly, the SNP rs161927 (P-value 0.000149), seventh-ranked for PC1, was positioned immediately downstream from the metabotropic glutamate receptor-7 gene (GRM7). As a previous GWAS of a European and Finnish sample set already suggested a role for GRM7 in ARHI, this study provides further evidence for the involvement of this gene.
| S-EPMC2987344 | biostudies-literature
Project description:We performed a genome-wide association study (GWAS) to identify the genes responsible for age-related hearing impairment (ARHI), the most common form of hearing impairment in the elderly. Analysis of common variants, with and without adjustment for stratification and environmental covariates, rare variants and interactions, as well as gene-set enrichment analysis, showed no variants with genome-wide significance. No evidence for replication of any previously reported genes was found. A study of the genetic architecture indicates for the first time that ARHI is highly polygenic in nature, with probably no major genes involved. The phenotype depends on the aggregated effect of a large number of SNPs, of which the individual effects are undetectable in a modestly powered GWAS. We estimated that 22% of the variance in our data set can be explained by the collective effect of all genotyped SNPs. A score analysis showed a modest enrichment in causative SNPs among the SNPs with a P-value below 0.01.
| S-EPMC4266741 | biostudies-literature
Project description:Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden.
| S-EPMC6811684 | biostudies-literature
Project description:Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0x10-11), 52Kb 3' of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8x10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9x10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2x10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI.
| S-EPMC5072625 | biostudies-literature
Project description:BackgroundAge-related hearing impairment (ARHI) is considered an unpreventable disorder. We aimed to detect specific genetic variants that are potentially related to ARHI via genome-wide association study (GWAS).MethodsA sample of 131 dizygotic twins was genotyped for single-nucleotide polymorphism- (SNP-) based GWAS. Gene-based test was performed using VEGAS2. Pathway enrichment analysis was conducted by PASCAL.ResultsThe twins are with a median age of 49 years, of which 128 were females and 134 were males. rs6633657 was the only SNP that reached the genome-wide significance level for better ear hearing level (BEHL) at 2.0 kHz (P = 1.19 × 10-8). Totally, 9, 10, 42, 7, 17, and 5 SNPs were suggestive evidence level for (P < 1 × 10-5) BEHLs at 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and pure tone average (PTA), respectively. Several promising genetic regions in chromosomes (near the C20orf196, AQPEP, UBQLN3, OR51B5, OR51I2, OR52D1, GLTP, GIT2, and PARK2) nominally associated with ARHI were identified. Gene-based analysis revealed 165, 173, 77, 178, 170, and 145 genes nominally associated with BEHLs at 0.5, 1.0, 2.0, 4.0, and 8.0 kHz and PTA, respectively (P < 0.05). For BEHLs at 0.5, 1.0, and 2.0 kHz, the main enriched pathways were phosphatidylinositol signaling system, regulation of ornithine decarboxylase, eukaryotic translation initiation factor (EIF) pathway, amine compound solute carrier (SLC) transporters, synthesis of phosphoinositides (PIPS) at the plasma membrane, and phosphatidylinositols (PI) metabolism.ConclusionsThe genetic variations reported herein are significantly involved in functional genes and regulatory domains that mediate ARHI pathogenesis. These findings provide clues for the further unraveling of the molecular physiology of hearing functions and identifying novel diagnostic biomarkers and therapeutic targets of ARHI.
| S-EPMC8314043 | biostudies-literature
Project description:BackgroundAge-related hearing impairment (ARHI) is a major disability among the elderly population. Heat shock proteins (HSPs) were found to be associated with ARHI in animal studies. The aim of this study was to analyze the associations of single nucleotide polymorphisms (SNPs) of HSP genes with ARHI in an elderly population in Taiwan.MethodsParticipants ≥65 years of age were recruited for audiometric tests and genetic analyses. The pure tone average (PTA) of the better hearing ear was calculated for ARHI evaluation. The associations of HSPA1L (rs2075800 and rs2227956), HSPA1A (rs1043618) and HSPA1B (rs2763979) with ARHI were analyzed in 146 ARHI-susceptible (cases) and 146 ARHI-resistant (controls) participants.ResultsThe "T" allele of HSPA1B rs2763979 showed a decreased risk of ARHI. The "TT" genotype of rs2763979 also showed a decreased risk of ARHI in the dominant hereditary model. For HSPA1L (rs2075800 and rs2227956) and HSPA1A (rs1043618), the haplotype "CAG" was related to a decreased risk of ARHI.ConclusionThese findings suggest that HSP70 polymorphisms are associated with susceptibility to ARHI in the elderly population.
| S-EPMC8086325 | biostudies-literature
Project description:BackgroundBi-parental mapping populations have been commonly utilized to identify and characterize quantitative trait loci (QTL) controlling resistance to soybean cyst nematode (SCN, Heterodera glycines Ichinohe). Although this approach successfully mapped a large number of SCN resistance QTL, it captures only limited allelic diversity that exists in parental lines, and it also has limitations for genomic resolution. In this study, a genome-wide association study (GWAS) was performed using a diverse set of 553 soybean plant introductions (PIs) belonging to maturity groups from III to V to detect QTL/genes associated with SCN resistance to HG Type 0.ResultsOver 45,000 single nucleotide polymorphism (SNP) markers generated by the SoySNP50K iSelect BeadChip (http// www.soybase.org ) were utilized for analysis. GWAS identified 14 loci distributed over different chromosomes comprising 60 SNPs significantly associated with SCN resistance. Results also confirmed six QTL that were previously mapped using bi-parental populations, including the rhg1 and Rhg4 loci. GWAS identified eight novel QTL, including QTL on chromosome 10, which we have previously mapped by using a bi-parental population. In addition to the known loci for four simple traits, such as seed coat color, flower color, pubescence color, and stem growth habit, two traits, like lodging and pod shattering, having moderately complex inheritance have been confirmed with great precision by GWAS.ConclusionsThe study showed that GWAS can be employed as an effective strategy for identifying complex traits in soybean and for narrowing GWAS-defined genomic regions, which facilitates positional cloning of the causal gene(s).
| S-EPMC4533770 | biostudies-literature
Project description:Genetic factors explain a majority of risk variance for age-related macular degeneration (AMD). While genome-wide association studies (GWAS) for late AMD implicate genes in complement, inflammatory and lipid pathways, the genetic architecture of early AMD has been relatively under studied. We conducted a GWAS meta-analysis of early AMD, including 4,089 individuals with prevalent signs of early AMD (soft drusen and/or retinal pigment epithelial changes) and 20,453 individuals without these signs. For various published late AMD risk loci, we also compared effect sizes between early and late AMD using an additional 484 individuals with prevalent late AMD. GWAS meta-analysis confirmed previously reported association of variants at the complement factor H (CFH) (peak P?=?1.5×10(-31)) and age-related maculopathy susceptibility 2 (ARMS2) (P?=?4.3×10(-24)) loci, and suggested Apolipoprotein E (ApoE) polymorphisms (rs2075650; P?=?1.1×10(-6)) associated with early AMD. Other possible loci that did not reach GWAS significance included variants in the zinc finger protein gene GLI3 (rs2049622; P?=?8.9×10(-6)) and upstream of GLI2 (rs6721654; P?=?6.5×10(-6)), encoding retinal Sonic hedgehog signalling regulators, and in the tyrosinase (TYR) gene (rs621313; P?=?3.5×10(-6)), involved in melanin biosynthesis. For a range of published, late AMD risk loci, estimated effect sizes were significantly lower for early than late AMD. This study confirms the involvement of multiple established AMD risk variants in early AMD, but suggests weaker genetic effects on the risk of early AMD relative to late AMD. Several biological processes were suggested to be potentially specific for early AMD, including pathways regulating RPE cell melanin content and signalling pathways potentially involved in retinal regeneration, generating hypotheses for further investigation.
| S-EPMC3543264 | biostudies-literature
Project description:BackgroundMaize (Zea Mays) is one of the world's most important crops. Hybrid maize lines resulted a major improvement in corn production in the previous and current centuries. Understanding the genetic mechanisms of the corn production associated traits greatly facilitate the development of superior hybrid varieties.ResultIn this study, four ear traits associated with corn production of Nested Association Mapping (NAM) population were analyzed using a full genetic model, and further, optimal genotype combinations and total genetic effects of current best lines, superior lines, and superior hybrids were predicted for each of the traits at four different locations. The analysis identified 21-34 highly significant SNPs (-log10P > 5), with an estimated total heritability of 37.31-62.34%, while large contributions to variations was due to dominance, dominance-related epistasis, and environmental interaction effects ([Formula: see text] 14.06% ~ 49.28%), indicating these factors contributed significantly to phenotypic variations of the ear traits. Environment-specific genetic effects were also discovered to be crucial for maize ear traits. There were four SNPs found for three ear traits: two for ear length and weight, and two for ear row number and length. Using the Enumeration method and the stepwise tuning technique, optimum multi-locus genotype combinations for superior lines were identified based on the information obtained from GWAS.ConclusionsPredictions of genetic breeding values showed that different genotype combinations in different geographical regions may be better, and hybrid-line variety breeding with homozygote and heterozygote genotype combinations may have a greater potential to improve ear traits.
| S-EPMC9673299 | biostudies-literature
Project description:Age-related hearing impairment (ARHI), or presbycusis, is a very common multifactorial disorder. Despite the knowledge that genetics play an important role in the etiology of human ARHI as revealed by heritability studies, to date, its precise genetic determinants remain elusive. Here we report the results of a cross-sectional family-based genetic study employing audiometric data. By using principal component analysis, we were able to reduce the dimensionality of this multivariate phenotype while capturing most of the variation and retaining biologically important features of the audiograms. We conducted a genome-wide association as well as a linkage scan with high-density SNP microarrays. Because of the presence of genetic population substructure, association testing was stratified after which evidence was combined by meta-analysis. No association signals reaching genome-wide significance were detected. Linkage analysis identified a linkage peak on 8q24.13-q24.22 for a trait correlated to audiogram shape. The signal reached genome-wide significance, as assessed by simulations. This finding represents the first locus for an ARHI trait.
| S-EPMC2556434 | biostudies-literature