Genome-wide association study and polygenic risk score analysis for hearing measures in children

Schmitz, Judith; Abbondanza, Filippo; Paracchini, Silvia

doi:10.1101/2020.07.22.215376

Cited by 4 publications

(3 citation statements)

References 99 publications

(151 reference statements)

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“…Our self-reported dyslexia diagnosis binary trait showed strong negative genetic correlations with quantitative reading and spelling measures, supporting the validity of this measure in the 23andMe cohort, and suggesting that reading skills and disorder are not qualitatively distinct. The positive genetic correlation between hearing difficulties and dyslexia is consistent with genetic correlations reported for childhood reading skill 42 , suggesting that hearing problems at an early age could affect acquisition of phonological processing skills.…”

Section: Discussionsupporting

confidence: 82%

Discovery of 42 genome-wide significant loci associated with dyslexia

Doust

Fontanillas²,

Eising³

et al. 2022

Nat Genet

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Reading and writing are crucial life skills but roughly one in ten children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet few convincing genetic markers have been found. Here we performed a genome-wide association study of 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls and identified 42 independent genome-wide significant loci: 15 in genes linked to cognitive ability/educational attainment, and 27 new and potentially more specific to dyslexia. We validated 23 loci (13 new) in independent cohorts of Chinese and European ancestry. Genetic etiology of dyslexia was similar between sexes, and genetic covariance with many traits was found, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Dyslexia polygenic scores explained up to 6% of variance in reading traits, and might in future contribute to earlier identification and remediation of dyslexia.

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Section: Discussionsupporting

confidence: 82%

Discovery of 42 genome-wide significant loci associated with dyslexia

Doust

Fontanillas²,

Eising³

et al. 2022

Nat Genet

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“…The same concept is illustrated also for common variants through polygenic risk scores (PRSs) analysis. For example, PRS for schizophrenia showed associations for a number of traits including poor cognitive outcomes ( 71 ) but also enhanced creativity ( 72 ), language performance ( 73 ) and hearing ( 74 ). Similarly, PRSs for general cognitive abilities show effects on reading and language measures ( 15 , 75–77 ).…”

Section: Discussionmentioning

confidence: 99%

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

Martinelli

Rice

Talcott

et al. 2021

Human Molecular Genetics

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At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N = 360) compared to cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24 046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N = 42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N = 1825; minimum p = 0.002 for nonword reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.

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“…The same concept is illustrated also for common variants through polygenic risk scores (PRS) analysis. For example, PRS for schizophrenia showed associations for a number of traits including poor cognitive outcomes (95) but also enhanced creativity (96), language performance (97) and hearing (98). Similarly, polygenic risk scores (PRS) for general cognitive abilities show effects on reading and language measures (15,99–101>.…”

Section: Discussionmentioning

confidence: 99%

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

Martinelli

Rice

Talcott

et al. 2021

Preprint

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View full text Add to dashboard Cite

At least 5% of children present unexpected difficulties in expressing and understanding spoken language. This condition is highly heritable and often co-occurs with other neurodevelopmental disorders such as dyslexia and ADHD. Through an exome sequencing analysis, we identified a rare missense variant (chr16:84405221, GRCh38.p12) in the ATP2C2 gene. ATP2C2 was implicated in language disorders by linkage and association studies, and exactly the same variant was reported previously in a different exome sequencing study for language impairment (LI). We followed up this finding by genotyping the mutation in cohorts selected for LI and comorbid disorders. We found that the variant had a higher frequency in LI cases (1.8%, N=360) compared to cohorts selected for dyslexia (0.8%, N = 520) and ADHD (0.7%, N = 150), which presented frequencies comparable to reference databases (0.9%, N = 24,046 gnomAD controls). Additionally, we observed that carriers of the rare variant identified from a general population cohort (N=42, ALSPAC cohort) presented, as a group, lower scores on a range of reading and language-related measures compared to controls (N=1825) (minimum p = 0.002 for nonword reading). ATP2C2 encodes for an ATPase (SPCA2) that transports calcium and manganese ions into the Golgi lumen. Our functional characterization suggested that the rare variant influences the ATPase activity of SPCA2. Thus, our results further support the role of ATP2C2 locus in language-related phenotypes and pinpoint the possible effects of a specific rare variant at molecular level.

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Genome-wide association study and polygenic risk score analysis for hearing measures in children

Cited by 4 publications

References 99 publications

Discovery of 42 genome-wide significant loci associated with dyslexia

Discovery of 42 genome-wide significant loci associated with dyslexia

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

A rare missense variant in theATP2C2gene is associated with language impairment and related measures

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