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Heritability and molecular genetic basis of acoustic startle eye blink and affectively modulated startle response: a genome-wide association study.

ABSTRACT: Acoustic startle responses have been studied extensively in relation to individual differences and psychopathology. We examined three indices of the blink response in a picture-viewing paradigm-overall startle magnitude across all picture types, and aversive and pleasant modulation scores-in 3,323 twins and parents. Biometric models and molecular genetic analyses showed that half the variance in overall startle was due to additive genetic effects. No single nucleotide polymorphism was genome-wide significant, but GRIK3 produced a significant effect when examined as part of a candidate gene set. In contrast, emotion modulation scores showed little evidence of heritability in either biometric or molecular genetic analyses. However, in a genome-wide scan, PARP14 produced a significant effect for aversive modulation. We conclude that, although overall startle retains potential as an endophenotype, emotion-modulated startle does not.

SUBMITTER: Vaidyanathan U

PROVIDER: S-EPMC4231542 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Heritability and molecular genetic basis of acoustic startle eye blink and affectively modulated startle response: a genome-wide association study.

Vaidyanathan Uma U Malone Stephen M SM Miller Michael B MB McGue Matt M Iacono William G WG

Psychophysiology 20141201 12

Acoustic startle responses have been studied extensively in relation to individual differences and psychopathology. We examined three indices of the blink response in a picture-viewing paradigm-overall startle magnitude across all picture types, and aversive and pleasant modulation scores-in 3,323 twins and parents. Biometric models and molecular genetic analyses showed that half the variance in overall startle was due to additive genetic effects. No single nucleotide polymorphism was genome-wid ...[more]

PMID: 25387708

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Project description:Latency of the acoustic startle response is the time required from the presentation of startling auditory stimulus until the startle response is elicited and provides an index of neural processing speed. Latency is prolonged in subjects with schizophrenia compared to controls in some but not all studies and is 68-90% heritable in baseline startle trials. In order to determine the genetic association with latency as a potential inroad into genetically based vulnerability to psychosis, we conducted a gene-based study of latency followed by an independent replication study of significant gene findings with a single-nucleotide polymorphism (SNP)-based analysis of schizophrenia and control subjects. 313 subjects from an urban population of low socioeconomic status with mixed psychiatric diagnoses were included in the gene-based study. Startle testing was conducted using a Biopac M150 system according to our published methods. Genotyping was performed with the Omni-Quad 1M or the Omni Express BeadChip. The replication study was conducted on 154 schizophrenia subjects and 123 psychiatric controls. Genetic analyses were conducted with Illumina Human Omni1-Quad and OmniExpress BeadChips. Twenty-nine SNPs were selected from four genes that were significant in the gene-based analysis and also associated with startle and/or schizophrenia in the literature. Linear regressions on latency were conducted, controlling for age, race, and diagnosis as a dichotomous variable. In the gene-based study, 2,870 genes demonstrated the evidence of association after correction for multiple comparisons (false discovery rate?<?0.05). Pathway analysis of these genes revealed enrichment for relevant biological processes including neural transmission (p?=?0.0029), synaptic transmission (p?=?0.0032), and neuronal development (p?=?0.024). The subsequent SNP-based replication analysis revealed a strong association of onset latency with the SNP rs901561 on the neuregulin gene (NRG1) in an additive model (beta?=?0.21, p?=?0.001), indicating that subjects with the AA and AG genotypes had slower mean latency than subjects with GG genotype. In conclusion, startle latency, a highly heritable measure that is slowed in schizophrenia, may be a useful biological probe for genetic contributions to psychotic disorders. Our analyses in two independent populations point to a significant prediction of startle latency by genetic variation in NRG1.

Project description:ImportanceMechanisms behind pigmentary glaucoma, a form of early-onset glaucoma that may potentially lead to severe visual impairment or blindness, are poorly understood.ObjectiveTo calculate the single-nucleotide polymorphism (SNP) heritability of pigmentary glaucoma and identify genetic associations with the disease.Design, setting and participantsThis genome-wide association study included affected individuals from Germany and control participants from the United Kingdom. Genome-wide information was obtained for patients with pigmentary glaucoma and control participants free of glaucoma by using the Illumina Human Omni Express Exome 8v1-2 chip and genomic imputation. The SNP heritability of pigmentary glaucoma was estimated through a restricted maximum likelihood analysis. Associations between the genetic variants and pigmentary glaucoma obtained from age, sex, and principal component-adjusted logistic regression models were compared with those of SNPs previously associated with other eye phenotypes using Pearson product-moment correlations. Data were collected from November 2008 to January 2018, and analysis was completed between April 2018 and August 2019.Main outcomes and measuresAn estimate of SNP-explained heritability for pigmentary glaucoma; correlations of effect sizes between pigmentary glaucoma and iris pigmentation and myopia; and correlations of effect sizes between pigmentary glaucoma and other eye phenotypes.ResultsA total of 227 affected individuals (mean [SD] age, 58.7 [13.3] years) and 291 control participants (mean [SD] age, 80.2 [4.9] years) were included; all were of European ancestry. The SNP heritability of pigmentary glaucoma was 0.45 (SE, 0.22; P = 6.15 × 10-10). Twelve SNPs previously reported with genome-wide significant associations with eye pigmentation were associated with pigmentary glaucoma's SNP heritability (4.9% SNP heritability; 0.022; P = 6.0 × 10-4). Pigmentary glaucoma SNP effect sizes were correlated moderately for myopia (r, 0.42 [95% CI, 0.14-0.63]; P = 4.3 × 10-3) and more strongly with those for iris pigmentation (r = -0.69 [95% CI, -0.91 to -0.20]; P = .01), although this was nonsignificant per a strict adjusted significance threshold (P < .01).Conclusions and relevanceThese findings support the conclusion that pigmentary glaucoma may have a genetic basis and be highly heritable. Variants associated with lighter eye color and myopia appear to be associated with increased risk of pigmentary glaucoma, but no shared genetic basis with primary open-angle glaucoma (or its quantitative endophenotype of cup-disc ratio) was observed.

Dataset Information

Heritability and molecular genetic basis of acoustic startle eye blink and affectively modulated startle response: a genome-wide association study.

Publications

Heritability and molecular genetic basis of acoustic startle eye blink and affectively modulated startle response: a genome-wide association study.

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