Biology subjects

Byrd, G. S.

Publications and source records attributed to Byrd, G. S..

4 recordsLinked to original sources

bioRxiv2025

Multi-ancestry Transcriptome-Wide Association Study Reveals Shared and Population-Specific Genetic Effects in Alzheimer's Disease

Alzheimers disease (AD) risk differs across ancestral populations, yet most genetic studies have focused on non-Hispanic White (NHW) cohorts. We conducted a multi-population transcriptome-wide association study (TWAS) using whole-blood RNA-seq and genotype data from NHW (n=235), African American (AA; n=224), and Hispanic (HISP; n=292) MAGENTA participants. Using SuShiE for multi-population cis-eQTL fine-mapping, we identified credible sets for 8,748 genes, improving fine-mapping precision relative to analyses using fewer populations. cis-eQTL effects were largely shared across populations, with a subset showing population-specific regulation. We performed population-stratified TWAS of AD and inverse variance-weighted meta-analysis, followed by gene-level TWAS fine-mapping (MA-FOCUS), prioritizing nine genes (FDR<0.05, PIP>0.8), including established AD loci (BIN1, PTK2B, DMPK) with broadly consistent effects across populations. At BIN1, fine-mapped cis-eQTL variants used in the TWAS prediction model highlighted rs11682128, which is only modestly correlated with the GWAS index SNP rs6733839 (r2 {approx} 0.34), demonstrating how integrating eQTL fine-mapping with TWAS can refine signals beyond sentinel GWAS variants. We also identified an association between COG4 expression and AD in NHW, implicating Golgi-related pathways. Using independent SuShiE-derived models from TOPMed MESA (PBMC), several signals replicated directionally across ancestries, with the strongest statistical support in NHW. Overall, multi-population eQTL fine-mapping improves model interpretability and helps resolve shared and population-specific regulatory mechanisms relevant to AD.

genomics↗

bioRxiv2024

African origin haplotype protective for Alzheimer's disease in APOEϵ4 carriers: exploring potential mechanisms

APOE{varepsilon}4 is the strongest genetic risk factor for Alzheimers disease (AD) with approximately 50% of AD patients carrying at least one APOE{varepsilon}4 allele. Our group identified a protective interaction between APOE{varepsilon}4 with the African-specific A allele of rs10423769, which reduces the AD risk effect of APOE{varepsilon}4 homozygotes by approximately 75%. The protective variant lies 2Mb from APOE in a region of segmental duplications (SD) of chromosome 19 containing a cluster of pregnancy specific beta-1 glycoprotein genes (PSGs) and a long non-coding RNA. Using both short and long read sequencing, we demonstrate that rs10423769_A allele lies within a unique single haplotype inside this region of segmental duplication. We identified the protective haplotype in all African ancestry populations studied, including both West and East Africans, suggesting the variant has an old origin. Long-read sequencing identified both structural and DNA methylation differences between the protective rs10423769_A allele and non-protective haplotypes. An expanded variable number tandem repeat (VNTR) containing multiple MEF2 family transcription factor binding motifs was found associated with the protective haplotype (p-value = 2.9e-10). These findings provide novel insights into the mechanisms of this African-origin protective variant for AD in APOE{varepsilon}4 carriers and supports the importance of including all ancestries in AD research.

genetics↗

bioRxiv2024

Methylation Clocks Do Not Predict Age or Alzheimer's Disease Risk Across Genetically Admixed Individuals

Epigenetic aging clocks based on DNA methylation patterns across the genome have emerged as a potential biomarker for risk of age-related diseases, like Alzheimers disease (AD), and environmental and social stressors. However, methylation clocks have not been comprehensively validated in genetically diverse individuals. Here we evaluate a set of first-, second-, and third-generation methylation clocks in 621 AD patients and matched controls from African American, Hispanic, and White cohorts. The clocks are less accurate at predicting age in genetically admixed cohorts compared to the White cohort, especially for those with substantial African ancestry. This decreased accuracy holds in >2,500 individuals of European and African ancestry from three additional datasets. The clocks also fail to consistently identify age acceleration in admixed AD cases compared to controls. To explore potential causes for the lack of generalization of the clocks, we intersected clock CpGs with methylation, germline genetic variants, and methylation QTL (meQTL) data from global populations. We find differential methylation between African and European ancestry individuals is common for clock CpGs. Genetic variants rarely disrupt clock CpGs between populations, but a substantial fraction of clock CpGs have meQTL with significantly higher frequencies in African genetic ancestries. Our results demonstrate that methylation clocks often fail to predict age and AD risk when applied across populations and suggest avenues for improving their portability by considering differences in genetic and epigenetic patterns across human populations.

genomics↗

bioRxiv2024

Gene expression and chromatin accessibility comparison in iPSC-derived microglia in African, European, and Amerindian genomes in Alzheimer's patients and controls.

Alzheimers disease (AD) risk differs between population groups, with African Americans and Hispanics being the most affected groups compared to non-Hispanic Whites. Genetic factors contribute significant risk to AD, but the genetic regulatory architectures (GRA) have primarily been studied in Europeans. Many AD genes are expressed in microglia; thus, we explored the impact of genetic ancestry (Amerindian (AI), African (AF), and European (EU)) on the GRA in iPSC-derived microglia from 13 individuals ([~]4 each with high global ancestry, AD and controls) through ATAC-seq and RNA-seq analyses. We identified several differentially accessible and expressed genes (2 and 10 AD-related, respectively) between ancestry groups. We also found a high correlation between the transcriptomes of iPSC-derived and brain microglia, supporting their use in human studies. This study provides valuable insights into genetically diverse microglia beyond the analysis of AD.

genomics↗