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Common genetic variants have associations with human cortical brain regions and risk of schizophrenia.

ABSTRACT: Schizophrenia is a highly heritable mental disorder and is reported to be associated with measurements in cortical regions of the human brain. In this study, we considered genome-wide association studies to uncover genetic effects on cortical regions and prodromal symptoms of schizophrenia. Specifically, area, thickness, and volume of 66 cortical regions derived from magnetic resonance imaging scans of 1,445 children and adolescents from the Philadelphia Neurodevelopmental Cohort were studied. Two common variants were identified as being associated with two prefrontal cortical regions (one significant variant rs11601331 on chromosome 11p11 for right rostral middle frontal gyral area, p?=?1.97?×?10 -8 ; one suggestive variant rs2345981 on chromosome 6q11 for left frontal pole gyral volume, p?=?2.07?×?10 -7 ), where the significance of rs11601331 was independently replicated on the Pediatric Imaging, Neurocognition, and Genetics study of size 1,239 (p?=?9.19?×?10 -3 ). Moreover, genetic effects on schizophrenia were investigated based on a sample of 8,719 subjects. The two identified variants rs11601331 and rs2345981 showed significant association with the longest prodromal symptoms duration (p?=?0.048 and p?=?0.027, respectively).

SUBMITTER: Bi X

PROVIDER: S-EPMC6559856 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Common genetic variants have associations with human cortical brain regions and risk of schizophrenia.

Bi Xuan X Feng Long L Wang Shiying S Lin Zijie Z Li Tengfei T Zhao Bingxin B Zhu Hongtu H Zhang Heping H

Genetic epidemiology 20190403 5

Schizophrenia is a highly heritable mental disorder and is reported to be associated with measurements in cortical regions of the human brain. In this study, we considered genome-wide association studies to uncover genetic effects on cortical regions and prodromal symptoms of schizophrenia. Specifically, area, thickness, and volume of 66 cortical regions derived from magnetic resonance imaging scans of 1,445 children and adolescents from the Philadelphia Neurodevelopmental Cohort were studied. T ...[more]

PMID: 30941828

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Project description:BackgroundThe impact of genetic variants on gene expression has been intensely studied at the transcription level, yielding in valuable insights into the association between genes and the risk of complex disorders, such as schizophrenia (SCZ). However, the downstream impact of these variants and the molecular mechanisms connecting transcription variation to disease risk are not well understood.ResultsWe quantitated ribosome occupancy in prefrontal cortex samples of the BrainGVEX cohort. Together with transcriptomics and proteomics data from the same cohort, we performed cis-Quantitative Trait Locus (QTL) mapping and identified 3,253 expression QTLs (eQTLs), 1,344 ribosome occupancy QTLs (rQTLs), and 657 protein QTLs (pQTLs) out of 7,458 genes quantitated in all three omics types from 185 samples. Of the eQTLs identified, only 34% have their effects propagated to the protein level. Further analysis on the effect size of prefrontal cortex eQTLs identified from an independent dataset showed clear post-transcriptional attenuation of eQTL effects. To investigate the biological relevance of the attenuated eQTLs, we identified 70 expression-specific QTLs (esQTLs), 51 ribosome-occupancy-specific QTLs (rsQTLs), and 107 protein-specific QTLs (psQTLs). Five of these omics-specific QTLs showed strong colocalization with SCZ GWAS signals, three of them are esQTLs. The limited number of GWAS colocalization discoveries from omics-specific QTLs and the apparent prevalence of eQTL attenuation prompted us to take a complementary approach to investigate the functional relevance of attenuated eQTLs. Using S-PrediXcan we identified 74 SCZ risk genes, 34% of which were novel, and 67% of these risk genes were replicated in a MR-Egger test. Notably, 52 out of 74 risk genes were identified using eQTL data and 70% of these SCZ-risk-gene-driving eQTLs show little to no evidence of driving corresponding variations at the protein level.ConclusionThe effect of eQTLs on gene expression in the prefrontal cortex is commonly attenuated post-transcriptionally. Many of the attenuated eQTLs still correlate with SCZ GWAS signal. Further investigation is needed to elucidate a mechanistic link between attenuated eQTLs and SCZ disease risk.

Project description:Most variants associated with complex phenotypes in genome-wide association studies (GWAS) do not directly index coding changes affecting protein structure. Instead they are hypothesized to influence gene regulation, with common variants associated with disease being enriched in regulatory domains including enhancers and regions of open chromatin. There is interest, therefore, in using epigenomic annotation data to identify the specific regulatory mechanisms involved and prioritize risk variants. We quantified lysine H3K27 acetylation (H3K27ac) - a robust mark of active enhancers and promoters that is strongly correlated with gene expression and transcription factor binding - across the genome in entorhinal cortex samples using chromatin immunoprecipitation followed by highly parallel sequencing (ChIP-seq). H3K27ac peaks were called using high quality reads combined across all samples and formed the basis of partitioned heritability analysis using LD score regression along with publicly-available GWAS results for seven psychiatric and neurodegenerative traits. Heritability for all seven brain traits was significantly enriched in these H3K27ac peaks (enrichment ranging from 1.09-2.13) compared to regions of the genome containing other active regulatory and functional elements across multiple cell types and tissues. The strongest enrichments were for amyotrophic lateral sclerosis (ALS) (enrichment = 2.19; 95% CI = 2.12-2.27), autism (enrichment = 2.11; 95% CI = 2.05-2.16) and major depressive disorder (enrichment = 2.04; 95% CI = 1.92-2.16). Much lower enrichments were observed for 14 non-brain disorders, although we identified enrichment in cortical H3K27ac domains for body mass index (enrichment = 1.16; 95% CI = 1.13-1.19), ever smoked (enrichment = 2.07; 95% CI = 2.04-2.10), HDL (enrichment = 1.53; 95% CI = 1.45-1.62) and trigylcerides (enrichment = 1.33; 95% CI = 1.24-1.42). These results indicate that risk alleles for brain disorders are preferentially located in regions of regulatory/enhancer function in the cortex, further supporting the hypothesis that genetic variants for these phenotypes influence gene regulation in the brain.

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Common genetic variants have associations with human cortical brain regions and risk of schizophrenia.

Publications

Common genetic variants have associations with human cortical brain regions and risk of schizophrenia.

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