Genome-wide Screen of Otosclerosis in Population Biobanks: 18 Loci and Shared Heritability with Skeletal Structure

Jt, Rämö; Kiiskinen, Tuomo; Karjalainen, Juha; Krebs, Kristi; Kurki, Mitja; Havulinna, Aki S.; Hämäläinen, Eija; Häppölä, Paavo; Hautakangas, Heidi; Kj, Karczewski; Kanai, Masahiro; Mägi, Reedik; Palta, Priit; Esko, Tõnu; Metspalu, Andres; Pirinen, Matti; Ripatti, Samuli; Milani, Lili; Mäkitie, Antti; Daly, Mark J.; Palotie, Aarno

doi:10.1101/2020.11.15.20227868

Cited by 4 publications

(14 citation statements)

References 62 publications

(124 reference statements)

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“…Apart from ACAN, several other bone morphogenetic genes have been associated with otosclerosis, such as TGFB1, BMP2 and BMP4 (Schrauwen et al 2008). In addition, a recent GWAS confirmed association of the TGFB1 pathway with otosclerosis, again suggesting the involvement of these bone morphogenetic genes (Rämö et al 2020).…”

Section: Discussionmentioning

confidence: 94%

“…The strongest associations have been found in TGFB1, BMP2, BMP4, COL1A1 and TNFRSF11B and possibly other genes plays a role in the pathogenesis of otosclerosis (Chen et al 2007;Khalfallah et al 2011;McKenna et al 1998;Priyadarshi et al 2015;Schrauwen et al 2012;Schrauwen et al 2008;Sommen et al 2014;Thys et al 2007a). To date, two genome wide association studies (GWAS) have been performed, showing strong association signals in RELN,11q13.1, TGFB1, MEPE and genes involved in bone remodeling (Rämö et al 2020;Schrauwen et al 2009). Next-generation sequencing (NGS) in otosclerosis research has led to succesful identification of pathogenic variants in MEPE (Schrauwen et al 2019) and SERPINF1 (Ziff et al 2016), although the pathogenic role of the latter is under debate (Valgaeren et al 2019).…”

Section: Introductionmentioning

confidence: 99%

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A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

et al. 2021

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In this study we investigated the association of ACAN variants with otosclerosis, a frequent cause of hearing loss among young adults.We sequenced the coding, 5'-UTR and 3'-UTR regions of ACAN in 1497 unrelated otosclerosis cases and 1437 matched controls from six different subpopulations. The association between variants in ACAN and the disease risk was tested through single variant and gene-based association tests.After correction for multiple testing, 14 variants were significantly associated with otosclerosis, ten of which represented independent association signals. Eight variants showed a consistent association across all subpopulations. Allelic odds ratios of the variants identified four predisposing and ten protective variants. Gene-based tests showed association of very rare variants in the 3'-UTR with the phenotype.The associated exonic variants are all located in the CS domain of ACAN and include both protective and predisposing variants with a broad spectrum of effect sizes and population frequencies. This includes variants with a strong effect size and low frequency, typical for monogenic diseases, to low effect size variants with high frequency, characteristic for common complex traits. This single-gene allelic spectrum with both protective and predisposing alleles is unique in the field of complex 4 diseases. In conclusion, these findings are a significant advancement to the understanding of the etiology of otosclerosis.

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Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

et al. 2021

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“…Seven genes were selected for resequencing based on the results of the GWAS by Rämö et al [ 18 ]. The replication effort prioritized (i) variants showing the strongest association with otosclerosis in the GWAS, (ii) variants in exonic regions, and (iii) variants in small genes, increasing the number of distinct genes that could be included in the study.…”

Section: Methodsmentioning

confidence: 99%

“…To date, only two GWA studies have been performed in otosclerosis. The most recent GWAS [ 18 ] was performed as a meta-analysis from three different biobanks: FinnGen, EstBB and UKBB, resulting in the identification of 18 loci associated with otosclerosis, including genes that were previously associated with otosclerosis, e.g., RELN , TGFβ1 and MEPE . In addition, 15 novel loci were identified, harboring several genes with an important role in regulation of the osteoblast and osteoclast, in bone mineralization or in various skeletal disorders.…”

Section: Introductionmentioning

confidence: 99%

Targeted Resequencing of Otosclerosis Patients from Different Populations Replicates Results from a Previous Genome-Wide Association Study

Tavernier

Vanpoucke

Schrauwen

et al. 2022

JCM

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Otosclerosis is one of the most common causes of hearing loss in young adults. It has a prevalence of 0.3–0.4% in the European population. Clinical symptoms usually occur between the second and fifth decade of life. Different studies have been performed to unravel the genetic architecture of the disease. Recently, a genome-wide association study (GWAS) identified 15 novel risk loci and replicated the regions of three previously reported candidate genes. In this study, seven candidate genes from the GWAS were resequenced using single molecule molecular inversion probes (smMIPs). smMIPs were used to capture the exonic regions and the 3′ and 5′ untranslated regions (UTR). Discovered variants were tested for association with the disease using single variant and gene-based association analysis. The single variant results showed that 13 significant variants were associated with otosclerosis. Associated variants were found in five of the seven genes studied here, including AHSG, LINC01482, MARK3, SUPT3H and RELN. Conversely, burden testing did not show a major role of rare variants in the disease. In conclusion, this study was able to replicate five out of seven candidate genes reported in the previous GWAS. This association is likely mainly driven by common variants.

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“…One such novel observation is a missense variant (p.Arg20Gln, AF 3%, gnomAD NFEE 0.7%) in SPDL1 with pleiotropic association with strongly increased risk of idiopathic pulmonary fibrosis (OR 3.1, p 1.0 * 10 -15 ) but protective with endpoint combining all cancers (OR 0.82, p 2.1 * 10 -15 ) 33 . Other associations described in separate manuscripts are associations between in frame deletion in MFGE8 and coronary atherosclerosis (p.Asn239dup, AF 2.9%, gnomAD NFSEE 0%, OR 0.74, p 5.4*10 -15 ) 34 , a frameshift variant in MEPE (p.Lys101IlefsTer26, AF 0.3%, gnomAD NFSEE 0.07%, OR 18.9, p 1.5 *10 -11 ) and otosclerosis 35 , and missense variant in ANGPTL7 and glaucoma (p.Arg220Cys, AF 4.2%, gnomAD NFSEE 0.06%, OR 0.7, p 7.2*10 -16 ) 19…”

Section: Mainmentioning

confidence: 96%

FinnGen: Unique genetic insights from combining isolated population and national health register data

Kurki

Karjalainen

Palta

et al. 2022

Preprint

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279

282

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Population isolates such as Finland provide benefits in genetic studies because the allelic spectrum of damaging alleles in any gene is often concentrated on a small number of low-frequency variants (0.1% ≤ minor allele frequency < 5%), which survived the founding bottleneck, as opposed to being distributed over a much larger number of ultra--rare variants. While this advantage is well-- established in Mendelian genetics, its value in common disease genetics has been less explored. FinnGen aims to study the genome and national health register data of 500,000 Finns, already reaching 224,737 genotyped and phenotyped participants. Given the relatively high median age of participants (63 years) and dominance of hospital-based recruitment, FinnGen is enriched for many disease endpoints often underrepresented in population-based studies (e.g., rarer immune-mediated diseases and late onset degenerative and ophthalmologic endpoints). We report here a genome-wide association study (GWAS) of 1,932 clinical endpoints defined from nationwide health registries. We identify genome--wide significant associations at 2,491 independent loci. Among these, finemapping implicates 148 putatively causal coding variants associated with 202 endpoints, 104 with low allele frequency (AF<10%) of which 62 were over two-fold enriched in Finland.We studied a benchmark set of 15 diseases that had previously been investigated in large genome-wide association studies. FinnGen discovery analyses were meta-analysed in Estonian and UK biobanks. We identify 30 novel associations, primarily low-frequency variants strongly enriched, in or specific to, the Finnish population and Uralic language family neighbors in Estonia and Russia.These findings demonstrate the power of bottlenecked populations to find unique entry points into the biology of common diseases through low-frequency, high impact variants. Such high impact variants have a potential to contribute to medical translation including drug discovery.

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Genome-wide Screen of Otosclerosis in Population Biobanks: 18 Loci and Shared Heritability with Skeletal Structure

Cited by 4 publications

References 62 publications

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

A wide range of protective and predisposing variants in aggrecan influence the susceptibility for otosclerosis

Targeted Resequencing of Otosclerosis Patients from Different Populations Replicates Results from a Previous Genome-Wide Association Study

FinnGen: Unique genetic insights from combining isolated population and national health register data

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