Gene burden analysis identifies genes associated with increased risk and severity of adult-onset hearing loss in a diverse hospital-based cohort

Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank–a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene–TCOF1, responsible for a syndromic form of congenital hearing loss–in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes (COL5A1, HMMR, RAPGEF3, and NNT) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases.

[1]  M. P. Concas,et al.  Genome-wide association meta-analysis identifies 48 risk variants and highlights the role of the stria vascularis in hearing loss , 2022, American journal of human genetics.

[2]  Michael F. Green,et al.  Mapping genomic loci implicates genes and synaptic biology in schizophrenia , 2022, Nature.

[3]  J. Marchini,et al.  Population-scale analysis of common and rare genetic variation associated with hearing loss in adults , 2021, Communications Biology.

[4]  D. Park,et al.  Association of Metabolic Syndrome with Sensorineural Hearing Loss , 2021, Journal of clinical medicine.

[5]  D. Ryugo,et al.  Diabetes mellitus and hearing loss: A review , 2021, Ageing Research Reviews.

[6]  L. Bastarache.  Using Phecodes for Research with the Electronic Health Record: From PheWAS to PheRS. , 2021, Annual review of biomedical data science.

[7]  D. Rader,et al.  A Genome-First Approach to Rare Variants in Dominant Postlingual Hearing Loss Genes in a Large Adult Population , 2021, Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery.

[8]  Hannes P. Eggertsson,et al.  The genetic architecture of age-related hearing impairment revealed by genome-wide association analysis , 2021, Communications biology.

[9]  Liuyi Dong,et al.  Epac1 Signaling Pathway Mediates the Damage and Apoptosis of Inner Ear Hair Cells after Noise Exposure in a Rat Model , 2021, Neuroscience.

[10]  Zhili Zheng,et al.  A generalized linear mixed model association tool for biobank-scale data , 2021, Nature Genetics.

[11]  Alexander Hanbo Li,et al.  Exome-wide evaluation of rare coding variants using electronic health records identifies new gene–phenotype associations , 2021, Nature Medicine.

[12]  Fabienne Wong Jun Tai,et al.  Ultrarare heterozygous pathogenic variants of genes causing dominant forms of early-onset deafness underlie severe presbycusis , 2020, Proceedings of the National Academy of Sciences.

[13]  G. Abecasis,et al.  A Novel Recurrent COL5A1 Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia , 2020, Arteriosclerosis, thrombosis, and vascular biology.

[14]  Elizabeth T. Cirulli,et al.  Genome-wide rare variant analysis for thousands of phenotypes in over 70,000 exomes from two cohorts , 2020, Nature Communications.

[15]  F. Williams,et al.  Genetics of age‐related hearing loss , 2020, Journal of neuroscience research.

[16]  M. Nalls,et al.  Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment , 2019, Scientific Reports.

[17]  C. Morton,et al.  GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank. , 2019, American journal of human genetics.

[18]  Max W. Y. Lam,et al.  Genome-wide Association Studies in Ancestrally Diverse Populations: Opportunities, Methods, Pitfalls, and Recommendations , 2019, Cell.

[19]  Scott M. Williams,et al.  The Missing Diversity in Human Genetic Studies , 2019, Cell.

[20]  Yang Ni,et al.  Polygenic prediction via Bayesian regression and continuous shrinkage priors , 2018, Nature Communications.

[21]  Alicia R. Martin,et al.  Clinical use of current polygenic risk scores may exacerbate health disparities , 2019, Nature Genetics.

[22]  Brian E. Cade,et al.  Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program , 2019, Nature.

[23]  R. Hertzano,et al.  Biological insights from multi-omic analysis of 31 genomic risk loci for adult hearing difficulty , 2019, bioRxiv.

[24]  K. Steel,et al.  Whole exome sequencing in adult-onset hearing loss reveals a high load of predicted pathogenic variants in known deafness-associated genes and identifies new candidate genes , 2018, BMC medical genomics.

[25]  Chunlei Liu,et al.  ClinVar: improving access to variant interpretations and supporting evidence , 2017, Nucleic Acids Res..

[26]  Christopher D. Brown,et al.  Increased burden of deleterious variants in essential genes in autism spectrum disorder , 2016, Proceedings of the National Academy of Sciences.

[27]  Trevor Hastie,et al.  REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. , 2016, American journal of human genetics.

[28]  N. Risch,et al.  A Large Genome-Wide Association Study of Age-Related Hearing Impairment Using Electronic Health Records , 2016, PLoS genetics.

[29]  Alan M. Kwong,et al.  Next-generation genotype imputation service and methods , 2016, Nature Genetics.

[30]  Y. Olgun,et al.  Variations in Multiple Syndromic Deafness Genes Mimic Non-syndromic Hearing Loss , 2016, Scientific Reports.

[31]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[32]  Carson C Chow,et al.  Second-generation PLINK: rising to the challenge of larger and richer datasets , 2014, GigaScience.

[33]  Gautier Koscielny,et al.  The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data , 2013, Nucleic Acids Res..

[34]  Melissa A. Basford,et al.  Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data , 2013, Nature Biotechnology.

[35]  J. Bos,et al.  Exchange protein activated by cAMP 1 (Epac1)‐deficient mice develop β‐cell dysfunction and metabolic syndrome , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[36]  Marylyn D Ritchie,et al.  BioBin: a bioinformatics tool for automating the binning of rare variants using publicly available biological knowledge , 2013, BMC Medical Genomics.

[37]  L. Garavelli,et al.  Clinical and molecular characterization of 40 patients with classic Ehlers–Danlos syndrome: identification of 18 COL5A1 and 2 COL5A2 novel mutations , 2013, Orphanet Journal of Rare Diseases.

[38]  Michael Boehnke,et al.  LocusZoom: regional visualization of genome-wide association scan results , 2010, Bioinform..

[39]  S. Leal,et al.  Mutations of ESRRB encoding estrogen-related receptor beta cause autosomal-recessive nonsyndromic hearing impairment DFNB35. , 2008, American journal of human genetics.

[40]  F. Ashcroft,et al.  Nicotinamide nucleotide transhydrogenase: a key role in insulin secretion. , 2006, Cell metabolism.

[41]  M. Lovett,et al.  TCOF1 gene encodes a putative nucleolar phosphoprotein that exhibits mutations in Treacher Collins Syndrome throughout its coding region. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[42]  J. Naeyaert,et al.  Mutations in the COL5A1 gene are causal in the Ehlers-Danlos syndromes I and II. , 1997, American journal of human genetics.

[43]  C. Petit.  Genes responsible for human hereditary deafness: symphony of a thousand , 1996, Nature Genetics.

[44]  K. Arnos,et al.  Genetic epidemiological studies of early-onset deafness in the U.S. school-age population. , 1993, American journal of medical genetics.

[45]  I. Rapin.  Hearing disorders. , 1993, Pediatrics in review.