A scalable Bayesian functional GWAS method accounting for multivariate quantitative functional annotations with applications for studying Alzheimer disease
Year: 2022
Type: article
Abstract: Existing methods for integrating functional annotations in GWAS to fine-map and prioritize potential causal variants are either limited to using non-overlapped categorical annotations, or limited by the computation burden of modeling genome-wide variants. To overcome these limitations, we propose a scalable Bayesian functional GWAS method to account for multivariate quantitative functional annotations (BFGWAS_QUANT), accompanied by a scalable computation algorithm enabling joint modeling of genome-wide variants. Simulation studies validated the performance of BFGWAS_QUANT for accurately quantifying annotation enrichment and improving GWAS power. Applying BFGWAS_QUANT to study five Alzheimer’s disease (AD) related phenotypes using individual-level GWAS data (n=∼1K), we found that histone modification annotations have higher enrichment than eQTL annotations for all considered phenotypes, with the highest enrichment in H3K27me3 (polycomb regression). We also found that cis-eQTL in microglia had higher enrichment than eQTL of bulk brain frontal cortex tissue for all considered phenotypes. A similar enrichment pattern was also identified using the IGAP summary-level GWAS data of AD (n=∼54K). The strongest known APOE E4 risk allele was identified for all five phenotypes and the APOE locus was validated using the IGAP data. BFGWAS_QUANT fine-mapped 32 significant variants from 1073 genome-wide significant variants in the IGAP data. We further demonstrated that the polygenic risk scores (PRS) using effect size estimates by BFGWAS_QUANT had similar prediction accuracy as other methods assuming a sparse causal model. Overall, BFGWAS_QUANT provides a useful GWAS tool for quantifying annotation enrichment and prioritizing potential causal variants.
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,300
Funders: Mayo Clinic, Illinois Department of Public Health, Mayo Foundation for Medical Education and Research, CurePSP, Rush University, Translational Genomics Research Institute, National Institutes of Health, National Institute on Aging, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Epidemiologic Study of Neural Reserve and Neurobiology of Aging, G124517134, G1258278173, G1282666458, G1379774384, G1435577123, G1457384572, Genetic Epidemiology of Cognitive Decline in an Aging Population Sample, G1791756382, G199972683, G2200385677, G2293782519, G2345704987, G249615658, Gene discovery in PSP by transcriptome, neuropathology and sequence analysis, G2642611343, G268727528, G289101313, Plasma AB as a Surrogate Genetic Marker for LOAD, G3036763132, G3103472451, Exploring the Role of the Brain Transcriptome in Cognitive Decline, G3153776459, G3255618601, G3643666687, Pathway discovery, validation and compound identification for Alzheimer's disease, Alzheimers Disease Patient Registry, Einstein Aging Study, G4097829506, G4298864339, G4311691470, G4356727394, G4440353152, G4741916379, Risk Factors, Pathology, and Clinical Expressions of AD, G4887214392, G5018925220, Rush Alzheimer's Disease Core Center, G5030236256, Alzheimer's Disease Genetics Consortium, G5333814337, G541333419, G5477913596, G5484535055, G5713958695, G578809140, G5952929075, Multi-omic network-directed proteoform discovery, dissection and functional validation to prioritize novel AD therapeutic targets, G6348385965, Florida Alzheimer's Disease Research, G6530347775, G6814118465, G6875889451, Genome wide association study of gene expression levels in Alzheimer's disease, Novel Bayesian statistical tools for integrating multi-omics data to help elucidate the genomic etiology of complex phenotypes, Global significance test based on quantile regression with applications to genomic studies of Alzheimer’s disease, Tau and Neurodegeneration II: A therapeutic target, G7479973302, A Systems Approach to Targeting Innate Immunity in AD, G7753556603, G8289575266, G860030259, G8629123209, G8762639507, G9000005508, G9000113025, G9000185113, G9000259012, G9000283702, G9000355711, Rush Alzheimer's Disease Research Center, G947960016, Mayo Alzheimer's Disease Research Center
OpenAlex ID: W4296182547