A Large-Scale Genome-Wide Study of Gene-Sleep Duration Interactions for Blood Pressure in 811,405 Individuals from Diverse Populations.

Although both short and long sleep duration are associated with elevated hypertension risk, our understanding of their interplay with biological pathways governing blood pressure remains limited. To address this, we carried out genome-wide cross-population gene-by-short-sleep and long-sleep duration interaction analyses for three blood pressure traits (systolic, diastolic, and pulse pressure) in 811,405 individuals from diverse population groups. We discover 22 novel gene-sleep duration interaction loci for blood pressure, mapped to genes involved in neurological, thyroidal, bone metabolism, and hematopoietic pathways. Non-overlap between short sleep (12) and long sleep (10) interactions underscores the plausibility of distinct influences of both sleep duration extremes in cardiovascular health. With several of our loci reflecting specificity towards population background or sex, our discovery sheds light on the importance of embracing granularity when addressing heterogeneity entangled in gene-environment interactions, and in therapeutic design approaches for blood pressure management.

Association of Race and Poverty Status With DNA Methylation-Based Age.

Importance: The Dunedin Pace of Aging Calculated From the Epigenome (DunedinPACE) measure is a newly constructed DNA methylation (DNAm) biomarker associated with morbidity, mortality, and adverse childhood experiences in several cohorts with European ancestry. However, there are few studies of the DunedinPACE measure among socioeconomically and racially diverse cohorts with longitudinal assessments. Objective: To investigate the association of race and poverty status with DunedinPACE scores in a socioeconomically diverse middle-aged cohort of African American and White participants. Design, Setting, and Participants: This longitudinal cohort study used data from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study. HANDLS is a population-based study of socioeconomically diverse African American and White adults aged 30 to 64 years at baseline in Baltimore, Maryland, with follow-up approximately every 5 years. The current study was restricted to 470 participants with blood samples at 2 time points: August 14, 2004, to June 22, 2009 (visit 1), and June 23, 2009, to September 12, 2017 (visit 2). Genome-wide DNAm was assessed at visit 1 (chronological age, 30-64 years) and visit 2. Data were analyzed from March 18, 2022, to February 9, 2023. Main Outcomes and Measures: DunedinPACE scores were estimated for each participant at 2 visits. DunedinPACE scores are values scaled to a mean of 1, interpretable with reference to a rate of 1 year of biological aging per 1 year of chronological aging. Linear mixed-model regression analysis was used to examine the trajectories of DunedinPACE scores by chronological age, race, sex, and poverty status. Results: Among 470 participants, the mean (SD) chronological age at visit 1 was 48.7 (8.7) years. Participants were balanced by sex (238 [50.6%] were men and 232 [49.4%] were women), race (237 [50.4%] African American and 233 [49.6%] White), and poverty status (236 [50.2%] living below poverty level and 234 [49.8%] living above poverty level). The mean (SD) time between visits was 5.1 (1.5) years. Overall, the mean (SD) DunedinPACE score was 1.07 (0.14), representing a 7% faster pace of biological aging than chronological aging. Linear mixed-effects regression analysis revealed an association between the 2-way interaction between race and poverty status (White race and household income below poverty level: ß = 0.0665; 95% CI, 0.0298-0.1031; P < .001) and significantly higher DunedinPACE scores and an association between quadratic age (age squared: ß = -0.0113; 95% CI, -0.0212 to -0.0013; P = .03) and significantly higher DunedinPACE scores. Conclusions and Relevance: In this cohort study, household income below poverty level and African American race were associated with higher DunedinPACE scores. These findings suggest that the DunedinPACE biomarker varies with race and poverty status as adverse social determinants of health. Consequently, measures of accelerated aging should be based on representative samples.

Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.

We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.

APOE gene region methylation is associated with cognitive performance in middle-aged urban adults.

Apolipoprotein (APOE) ε4 allele is a strong risk factor for Alzheimer's disease (AD) and cognitive decline. Epigenetic modifications such as DNA methylation (DNAm) play a central role in cognition. This study sought to identify DNAm sites in the APOE genomic region associated with cognitive performance in a racially diverse middle-aged cohort (n = 411). Cognitive performance was measured by 11 standard neuropsychological tests. Two CpG sites were associated with the Card Rotation and Benton Visual Retention cognitive tests. The methylation level of the CpG site cg00397545 was associated with Card Rotation Test score (p = 0.000177) and a novel CpG site cg10178308 was associated with Benton Visual Retention Test score (p = 0.000084). Significant associations were observed among the dietary inflammatory index, which reflects the inflammatory potential of the diet, cognitive performance and the methylation level of several CpG sites. Our results indicate that DNAm in the APOE genomic area is correlated with cognitive performance and may presage cognitive decline.

Associations between race, APOE genotype, cognition, and mortality among urban middle-aged white and African American adults.

We examined associations between cognition and mortality and how these relationships vary by race and Apolipoprotein E (APOE) genotype, in a longitudinal study of 2346 middle-aged White and African American adults (30-64 years at baseline) from the Healthy Aging in Neighborhoods of Diversity across the Life Span cohort study. Baseline cognition spanned global mental status, and several domains obtained using principal components analysis (PCA; PCA1: verbal memory/fluency; PCA2: attention/working memory; PCA3: executive function/visuo-spatial abilities). Cox regression models evaluated associations between cognition and all-cause and cardiovascular disease (CVD)-mortality. Interactions between cognition and APOE2 as well as APOE4 allelic dose were tested, and race was a key effect modifier. Higher APOE4 dose was associated with increased CVD-mortality (hazard ratio [HR] per allele = 1.37; 95% CI 1.01-1.86, p = 0.041); APOE2 dosage's association with CVD-mortality was non-significant (HR = 0.60; 95% CI 0.35-1.03, p = 0.065). Higher PCA3 was associated with lower all-cause (HR = 0.93; 95% CI 0.87-0.99, p = 0.030) and CVD (HR = 0.85; 95% CI 0.77-0.95, p = 0.001) mortality risks, the latter association being more pronounced among Whites. PCA2 interacted synergistically with APOE2 dosage, reducing risks for all-cause mortality (PCA2 × APOE2: - 0.33 ± 0.13, p = 0.010) and CVD mortality (PCA2 × APOE2: - 0.73 ± 0.31, p = 0.019). In conclusion, greater executive function/visuo-spatial abilities were associated with reduced CVD-specific mortality, particularly among Whites. Greater "attention/working memory" coupled with higher APOE2 dosage was linked with reduced all-cause and CVD mortality risks.

Effect of Temperature and Maternal Age on Recombination Rate in Cattle.

Meiotic recombination is a fundamental biological process that facilitates meiotic division and promotes genetic diversity. Recombination is phenotypically plastic and affected by both intrinsic and extrinsic factors. The effect of maternal age on recombination rates has been characterized in a wide range of species, but the effect's direction remains inconclusive. Additionally, the characterization of temperature effects on recombination has been limited to model organisms. Here we seek to comprehensively determine the impact of genetic and environmental factors on recombination rate in dairy cattle. Using a large cattle pedigree, we identified maternal recombination events within 305,545 three-generation families. By comparing recombination rate between parents of different ages, we found a quadratic trend between maternal age and recombination rate in cattle. In contrast to either an increasing or decreasing trend in humans, cattle recombination rate decreased with maternal age until 65 months and then increased afterward. Combining recombination data with temperature information from public databases, we found a positive correlation between environmental temperature during fetal development of offspring and recombination rate in female parents. Finally, we fitted a full recombination rate model on all related factors, including genetics, maternal age, and environmental temperatures. Based on the final model, we confirmed the effect of maternal age and environmental temperature during fetal development of offspring on recombination rate with an estimated heritability of 10% (SE = 0.03) in cattle. Collectively, we characterized the maternal age and temperature effects on recombination rate and suggested the adaptation of meiotic recombination to environmental stimuli in cattle. Our results provided first-hand information regarding the plastic nature of meiotic recombination in a mammalian species.

Race, APOE genotypes, and cognitive decline among middle-aged urban adults.

BACKGROUND: Associations of Apolipoprotein (APOE) ε2 or ε4 (APOE2 or APOE4) dosages with cognitive change may differ across racial groups. METHODS: Longitudinal data on 1770 middle-aged White and African American adults was compiled from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS 2004-2013) study. APOE2 and APOE4 dosages were the two main exposures, while v1 and annual rate of change in cognitive performance (between v1 and v2) on 11 test scores were the main outcomes of interest (v1: 2004-2009 and v2: 2009-2013). Mixed-effects linear regression models were conducted adjusting for socio-demographic, lifestyle, and health-related potential confounders. Race (African American vs. White) and sex within racial groups were main effect modifiers. RESULTS: Upon adjustment for multiple testing and potential confounders, APOE4 allelic dosage was associated with faster decline on a test of verbal memory among Whites only (CVLT-List A: γ12 = - 0.363 ± 0.137, p = 0.008), but not among African Americans. In contrast, among African American women, APOE4 dosage was linked to slower decline on a test of attention (BTA: γ12 = + 0.106 ± 0.035, p = 0.002), while no association was detected among African American men. APOE2 and APOE4 dosages showed inconsistent results in other domains of cognition overall and across racial groups that did not survive correction for multiple testing. CONCLUSIONS: In conclusion, APOE4 dosage was associated with faster decline on a test of verbal memory among Whites only, while exhibiting a potential protective effect among African American women in the domain of attention. Further longitudinal studies are needed to replicate our race and sex-specific findings.

Characterization of recombination features and the genetic basis in multiple cattle breeds.

BACKGROUND: Crossover generated by meiotic recombination is a fundamental event that facilitates meiosis and sexual reproduction. Comparative studies have shown wide variation in recombination rate among species, but the characterization of recombination features between cattle breeds has not yet been performed. Cattle populations in North America count millions, and the dairy industry has genotyped millions of individuals with pedigree information that provide a unique opportunity to study breed-level variations in recombination. RESULTS: Based on large pedigrees of Jersey, Ayrshire and Brown Swiss cattle with genotype data, we identified over 3.4 million maternal and paternal crossover events from 161,309 three-generation families. We constructed six breed- and sex-specific genome-wide recombination maps using 58,982 autosomal SNPs for two sexes in the three dairy cattle breeds. A comparative analysis of the six recombination maps revealed similar global recombination patterns between cattle breeds but with significant differences between sexes. We confirmed that male recombination map is 10% longer than the female map in all three cattle breeds, consistent with previously reported results in Holstein cattle. When comparing recombination hotspot regions between cattle breeds, we found that 30% and 10% of the hotspots were shared between breeds in males and females, respectively, with each breed exhibiting some breed-specific hotspots. Finally, our multiple-breed GWAS found that SNPs in eight loci affected recombination rate and that the PRDM9 gene associated with hotspot usage in multiple cattle breeds, indicating a shared genetic basis for recombination across dairy cattle breeds. CONCLUSIONS: Collectively, our results generated breed- and sex-specific recombination maps for multiple cattle breeds, provided a comprehensive characterization and comparison of recombination patterns between breeds, and expanded our understanding of the breed-level variations in recombination features within an important livestock species.

Construction of PRDM9 allele-specific recombination maps in cattle using large-scale pedigree analysis and genome-wide single sperm genomics.

PRDM9 contributes to hybrid sterility and species evolution. However, its role is to be confirmed in cattle, a major domesticated livestock species. We previously found an association near PRDM9 with cattle recombination features, but the causative variants are still unknown. Using millions of genotyped cattle with pedigree information, we characterized five PRDM9 alleles and generated allele-specific recombination maps. By examining allele-specific recombination patterns, we observed the impact of PRDM9 on global distribution of recombination, especially in the two ends of chromosomes. We also showed strong associations between recombination hotspot regions and functional mutations within PRDM9 zinc finger domain. More importantly, we found one allele of PRDM9 to be very different from others in both protein composition and recombination landscape, indicating the causative role of this allele on the association between PRDM9 and cattle recombination. When comparing recombination maps from sperm and pedigree data, we observed similar genome-wide recombination patterns, validating the quality of pedigree-based results. Collectively, these evidence supported PRDM9 alleles as causal variants for the reported association with cattle recombination. Our study comprehensively surveyed the bovine PRDM9 alleles, generated allele-specific recombination maps, and expanded our understanding of the role of PRDM9 on genome distribution of recombination.

Dissection of additive, dominance, and imprinting effects for production and reproduction traits in Holstein cattle.

BACKGROUND: Although genome-wide association and genomic selection studies have primarily focused on additive effects, dominance and imprinting effects play an important role in mammalian biology and development. The degree to which these non-additive genetic effects contribute to phenotypic variation and whether QTL acting in a non-additive manner can be detected in genetic association studies remain controversial. RESULTS: To empirically answer these questions, we analyzed a large cattle dataset that consisted of 42,701 genotyped Holstein cows with genotyped parents and phenotypic records for eight production and reproduction traits. SNP genotypes were phased in pedigree to determine the parent-of-origin of alleles, and a three-component GREML was applied to obtain variance decomposition for additive, dominance, and imprinting effects. The results showed a significant non-zero contribution from dominance to production traits but not to reproduction traits. Imprinting effects significantly contributed to both production and reproduction traits. Interestingly, imprinting effects contributed more to reproduction traits than to production traits. Using GWAS and imputation-based fine-mapping analyses, we identified and validated a dominance association signal with milk yield near RUNX2, a candidate gene that has been associated with milk production in mice. When adding non-additive effects into the prediction models, however, we observed little or no increase in prediction accuracy for the eight traits analyzed. CONCLUSIONS: Collectively, our results suggested that non-additive effects contributed a non-negligible amount (more for reproduction traits) to the total genetic variance of complex traits in cattle, and detection of QTLs with non-additive effect is possible in GWAS using a large dataset.

Ruminant-specific multiple duplication events of PRDM9 before speciation.

BACKGROUND: Understanding the genetic and evolutionary mechanisms of speciation genes in sexually reproducing organisms would provide important insights into mammalian reproduction and fitness. PRDM9, a widely known speciation gene, has recently gained attention for its important role in meiotic recombination and hybrid incompatibility. Despite the fact that PRDM9 is a key regulator of recombination and plays a dominant role in hybrid incompatibility, little is known about the underlying genetic and evolutionary mechanisms that generated multiple copies of PRDM9 in many metazoan lineages. RESULTS: The present study reports (1) evidence of ruminant-specific multiple gene duplication events, which likely have had occurred after the ancestral ruminant population diverged from its most recent common ancestor and before the ruminant speciation events, (2) presence of three copies of PRDM9, one copy (lineages I) in chromosome 1 (chr1) and two copies (lineages II & III) in chromosome X (chrX), thus indicating the possibility of ancient inter- and intra-chromosomal unequal crossing over and gene conversion events, (3) while lineages I and II are characterized by the presence of variable tandemly repeated C2H2 zinc finger (ZF) arrays, lineage III lost these arrays, and (4) C2H2 ZFs of lineages I and II, particularly the amino acid residues located at positions -1, 3, and 6 have evolved under strong positive selection. CONCLUSIONS: Our results demonstrated two gene duplication events of PRDM9 in ruminants: an inter-chromosomal duplication that occurred between chr1 and chrX, and an intra-chromosomal X-linked duplication, which resulted in two additional copies of PRDM9 in ruminants. The observation of such duplication between chrX and chr1 is rare and may possibly have happened due to unequal crossing-over millions of years ago when sex chromosomes were independently derived from a pair of ancestral autosomes. Two copies (lineages I & II) are characterized by the presence of variable sized tandem-repeated C2H2 ZFs and evolved under strong positive selection and concerted evolution, supporting the notion of well-established Red Queen hypothesis. Collectively, gene duplication, concerted evolution, and positive selection are the likely driving forces for the expansion of ruminant PRDM9 sub-family.

Effect of sex, age and genetics on crossover interference in cattle.

Crossovers generated by homologous recombination ensure proper chromosome segregation during meiosis. Crossover interference results in chiasmata being more evenly distributed along chromosomes, but the mechanism underlying crossover interference remains elusive. Based on large pedigrees of Holstein and Jersey cattle with genotype data, we extracted three-generation families, including 147,327 male and 71,687 female meioses in Holstein, and 108,163 male and 37,008 female meioses in Jersey, respectively. We identified crossovers in these meioses and fitted the Housworth-Stahl "interference-escape" model to study crossover interference patterns in the cattle genome. Our result reveals that the degree of crossover interference is stronger in females than in males. We found evidence for inter-chromosomal variation in the level of crossover interference, with smaller chromosomes exhibiting stronger interference. In addition, crossover interference levels decreased with maternal age. Finally, sex-specific GWAS analyses identified one locus near the NEK9 gene on chromosome 10 to have a significant effect on crossover interference levels. This locus has been previously associated with recombination rate in cattle. Collectively, this large-scale analysis provided a comprehensive description of crossover interference across chromosome, sex and age groups, identified associated candidate genes, and produced useful insights into the mechanism of crossover interference.

Cattle Sex-Specific Recombination and Genetic Control from a Large Pedigree Analysis.

Meiotic recombination is an essential biological process that generates genetic diversity and ensures proper segregation of chromosomes during meiosis. From a large USDA dairy cattle pedigree with over half a million genotyped animals, we extracted 186,927 three-generation families, identified over 8.5 million maternal and paternal recombination events, and constructed sex-specific recombination maps for 59,309 autosomal SNPs. The recombination map spans for 25.5 Morgans in males and 23.2 Morgans in females, for a total studied region of 2,516 Mb (986 kb/cM in males and 1,085 kb/cM in females). The male map is 10% longer than the female map and the sex difference is most pronounced in the subtelomeric regions. We identified 1,792 male and 1,885 female putative recombination hotspots, with 720 hotspots shared between sexes. These hotspots encompass 3% of the genome but account for 25% of the genome-wide recombination events in both sexes. During the past forty years, males showed a decreasing trend in recombination rate that coincided with the artificial selection for milk production. Sex-specific GWAS analyses identified PRDM9 and CPLX1 to have significant effects on genome-wide recombination rate in both sexes. Two novel loci, NEK9 and REC114, were associated with recombination rate in both sexes, whereas three loci, MSH4, SMC3 and CEP55, affected recombination rate in females only. Among the multiple PRDM9 paralogues on the bovine genome, our GWAS of recombination hotspot usage together with linkage analysis identified the PRDM9 paralogue on chromosome 1 to be associated in the U.S. Holstein data. Given the largest sample size ever reported for such studies, our results reveal new insights into the understanding of cattle and mammalian recombination.