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- W4387476610 abstract "Despite the success of genome-wide association studies (GWAS) of complex diseases, risk genes and the underlying molecular/cellular mechanisms remain largely unknown. We have recently developed an approach to map putatively functional variants that affect chromatin accessibility and gene expression by comparing the quantitative measurements of open chromatin between the two alleles of a heterozygous SNP, i.e., allele-specific open chromatin (ASoC) mapping (Zhang et al., Science 2020). To systematically identify functional risk variants/genes for brain disorders, we performed ASoC mapping in human induced pluripotent stem cell (hiPSC)-derived glutamatergic (n=41), GABAergic (n=34), and dopaminergic (n=30) neurons, astrocytes (n=18), and microglia (n=38). We found open chromatin regions were enriched for GWAS risk variants for schizophrenia (SZ), bipolar (BP) and major depression disorders (MDD) in neurons, and for Alzheimer's diseases (AD) in microglia. We identified abundant (8,066-72,291) cell-type-specific ASoC SNPs, which were enriched (1.5∼2.8-fold) for brain eQTLs, implying their functionality in regulating gene expression. Our TORUS SNP heritability enrichment analysis for AsoC SNPs further showed that neuronal AsoC SNPs were strongly enriched for GWAS risk of neuropsychiatric disorders with the strongest enrichment for SZ, while the microglia AsoC SNPs were most strongly enriched for AD GWAS risk. In total, 58 SZ risk variants at 47 loci, 23 BD risk variants at 11 loci, and 19 MDD risk variants at 16 loci showed ASoC in neurons, while 38 AD risk variants at 20 loci showed ASoC in microglia. Combining brain eQTL and promoter-capture Hi-C (Micro-C) data with our single-neuron multiplex CRISPRi/RNA-seq, we mapped cis-target genes for selected ASoC SNPs. To tie ASoC with functionality, we CRISPR-edited the strongest ASoC SNP rs2027349 at a SZ locus near VPS45, and found that rs2027349 cis-regulated multiple genes that synergistically contributed to the SZ-relevant neural phenotypes. Our study provides a framework for prioritizing functional GWAS risk variants that affect chromatin accessibility and for identifying downstream target genes and cellular phenotypes." @default.
- W4387476610 created "2023-10-11" @default.
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- W4387476610 date "2023-10-01" @default.
- W4387476610 modified "2023-10-16" @default.
- W4387476610 title "64. CHROMATIN ACCESSIBILITY MAPPING IN HIPSC IMPLICATES FUNCTIONAL GWAS RISK VARIANTS AND TARGET GENES FOR NEUROPSYCHIATRIC DISORDERS AND ALZHEIMER'S DISEASE" @default.
- W4387476610 doi "https://doi.org/10.1016/j.euroneuro.2023.08.169" @default.
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