Biology subjects

Province, M. A.

Publications and source records attributed to Province, M. A..

8 recordsLinked to original sources

bioRxiv2026

Erythrocyte Count and the Human Natural Lifespan Limit: Evidence from the Long Life Family Study

Erythropoiesis is the most replication-intensive process in the body. Its lifelong replicative demands may erode hematopoietic cells replicative capacity, leading to a decline in erythrocyte count (EC) in older adults and limiting their lifespan. We examined the relationship between EC and mortality among 1,620 participants aged [≥]70 years in the Long Life Family Study and found that lower EC further augmented the exponential, age-dependent rise in mortality. We identified an EC threshold (ECT) (3.8x1012/L) below which mortality was amplified (p=9.3x10-6). As EC declined with age (p=8.2x10-18), it fell below this threshold in many participants, sharply increasing their mortality risk. This mortality-based ECT emerged from modeling, independent of the World Health Organization anemia definition, which is based on statistical thresholds (5th centiles) of hemoglobin distribution in populations [≤] 65 years. Thus, declining EC may be one of the biological factors imposing a natural lifespan limit on many older adults.

physiology↗

bioRxiv2025

Construction of Multi-Modal Transcriptome-Small Molecule Interaction Networks from High-Throughput Measurements to Study Human Complex Traits

We present Gene-Embedded Multi-modal Networks (GEM-Net), a semi-supervised framework for constructing multi-modal networks centered on genes. GEM-Net uses gene-level modules and selectively incorporates heterogeneous omics profiles using a correlated meta-analysis strategy that accounts for scale imbalance, missingness, and intra-modular correlation. Prior to network inference, we developed a harmonized data processing protocol that adjusts each omic layer independently through a shared mathematical workflow involving transformation, dimensionality reduction, and regression-based covariate adjustment. GEM-Net modules were inferred and benchmarked against unsupervised methods using transcriptomic, metabolomic, and lipidomic data from the Long Life Family Study (LLFS), a unique cohort enriched for exceptional familial longevity and health. GEM-Net modules were more diverse and biologically interpretable, with stronger support from protein- protein interactions, transcriptional regulation, and metabolic annotations. Applying GEM-Net to metabolic health in LLFS revealed an axis between the microbiome-derived metabolite N-acetylglycine and immune genes (FCER1A, HDC, CPA3, MS4A2) associated with improved insulin sensitivity and reduced inflammation in healthy older individuals. GEM-Nets offer a reusable reference from a long-lived population and a generalizable framework for multi-omics discovery. https://doi.org/10.5281/zenodo.15003731.

systems biology↗

bioRxiv2024

A Paradigm For Calling Sequence In Families: The Long Life Family Study

Over Several years, we have developed a system for assuring the quality of whole genome sequence (WGS) data in the LLFS families. We have focused on providing data to identify germline genetic variants with the aim of releasing as many variants on as many individuals as possible. We aim to assure the quality of the individual calls. The availability of family data has enabled us to use and validate some filters not commonly used in population-based studies. We developed slightly different procedures for the autosomal, X, Y, and Mitochondrial (MT) chromosomes. Some of these filters are specific to family data, but some can be used with any WGS data set. We also describe the procedure we use to construct linkage markers from the SNP sequence data and how we compute IBD values for use in linkage analysis.

genetics↗

bioRxiv2024

A Novel Gene ARHGAP44 for Longitudinal Changes in Glycated Hemoglobin (HbA1c) in Subjects without Type 2 Diabetes: Evidence from the Long Life Family Study (LLFS) and the Framingham Offspring Study (FOS)

Glycated hemoglobin (HbA1c) indicates average glucose levels over three months and is associated with insulin resistance and type 2 diabetes (T2D). Longitudinal changes in HbA1c ({Delta}HbA1c) are also associated with aging processes, cognitive performance, and mortality. We analyzed {Delta}HbA1c in 1,886 non-diabetic Europeans from the Long Life Family Study to uncover gene variants influencing {Delta}HbA1c. Using growth curve modeling adjusted for multiple covariates, we derived {Delta}HbA1c and conducted linkage-guided sequence analysis. Our genome-wide linkage scan identified a significant locus on 17p12. In-depth analysis of this locus revealed a variant rs56340929 (explaining 27% of the linkage peak) in the ARHGAP44 gene that was significantly associated with {Delta}HbA1c. RNA transcription of ARHGAP44 was associated with {Delta}HbA1c. The Framingham Offspring Study data further supported these findings on the gene level. Together, we found a novel gene ARHGAP44 for {Delta}HbA1c in family members without T2D. Follow-up studies using longitudinal omics data in large independent cohorts are warranted.

genetics↗

bioRxiv2021

Genome-wide analysis of mitochondrial DNA copy number reveals multiple loci implicated in nucleotide metabolism, platelet activation, and megakaryocyte proliferation

Mitochondrial DNA copy number (mtDNA-CN) measured from blood specimens is a minimally invasive marker of mitochondrial function that exhibits both inter-individual and intercellular variation. To identify genes involved in regulating mitochondrial function, we performed a genome-wide association study (GWAS) in 465,809 White individuals from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (UKB). We identified 133 SNPs with statistically significant, independent effects associated with mtDNA-CN across 100 loci. A combination of fine-mapping, variant annotation, and co-localization analyses were used to prioritize genes within each of the 133 independent sites. Putative causal genes were enriched for known mitochondrial DNA depletion syndromes (p = 3.09 x 10-15) and the gene ontology (GO) terms for mtDNA metabolism (p = 1.43 x 10-8) and mtDNA replication (p = 1.2 x 10-7). A clustering approach leveraged pleiotropy between mtDNA-CN associated SNPs and 41 mtDNA-CN associated phenotypes to identify functional domains, revealing three distinct groups, including platelet activation, megakaryocyte proliferation, and mtDNA metabolism. Finally, using mitochondrial SNPs, we establish causal relationships between mitochondrial function and a variety of blood cell related traits, kidney function, liver function and overall (p = 0.044) and non-cancer mortality (p = 6.56 x 10-4).

genetics↗

bioRxiv2019

Role of Rare and Low Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels

BackgroundAlcohol intake influences plasma lipid levels and such effects may be modulated by genetic variants. ObjectiveWe aimed to characterize the role of aggregated rare and low-frequency variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels. DesignIn the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, fasting plasma triglycerides (TG), and high- and low-density lipoprotein cholesterol (HDL-c and LDL-c) were measured in 34,153 European Americans from five discovery studies and 32,275 individuals from six replication studies. Rare and low-frequency protein coding variants (minor allele frequency [≤] 5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction (GxE) test and a joint test of genetic main and GxE interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least two drinks per week, were considered. ResultsWe discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (PCSK9, LPA, LPL, LIPG, ANGPTL4, APOB, APOC3 and CD300LG) remained significant after conditioning on the common index single nucleotide polymorphism (SNP) identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on TG was discovered at a Bonferroni corrected significance level (p-value <5x10-5) and replicated (p-value <0.013 for the interaction test) in SMC5. ConclusionsIn conclusion, this study applied new gene-based statistical approaches to uncover the role of rare and low-frequency variants in gene-alcohol consumption interactions on lipid levels.

epidemiology↗

bioRxiv2017

Identifying the phenotypic effect of rare variants by including between-pedigree coancestry in variance components linkage analysis

The contribution of rare variants to disease burden has become an important focus in genetic epidemiology. These effects are difficult to detect in population-based datasets, and as a result, interest in family-based study designs has resurfaced. Linkage analysis tools will need to be updated to accommodate the scale of data generated by modern genotyping and sequencing technologies.\n\nIn conventional linkage analysis individuals in different pedigrees are assumed to be independent of each other. However, cryptic relatedness is often present in populations and haplotypes that harbor rare variants may be shared between pedigrees as well as within them.\n\nWith millions of polymorphisms, Identity-by-descent (IBD) states across the genome can now be inferred without use of pedigree information. This is done by identifying long runs of identical-by-state genotypes which are unlikely to arise without IBD. Previously, IBD had to be estimated in pedigrees from recombination events in a sparse set of markers.\n\nWe present a method for variance-components linkage that can incorporate large number of markers and allows for between-pedigree relatedness. We replace the IBD matrix generated from pedigree-based analysis with one generated from a genotype-based method. All pedigrees in a dataset are considered jointly, allowing between-pedigree IBD to be included in the model.\n\nIn simulated data, we show that power is increased in the scenario when there is a haplotype shared IBD between members of different pedigrees. If there is no between-pedigree IBD, the analysis reduces to conventional variance-components analysis. By determining IBD states by long runs of dense IBS genotypes, linkage signals can be determined from their physical position, allowing more precise localization.

genetics↗

bioRxiv2017

Meta-analysis of exome array data identifies six novel genetic loci for lung function

Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease (COPD). We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV1), forced vital capacity (FVC) and the ratio of FEV1 to FVC (FEV1/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals. We identified significant (P<2{middle dot}8x10-7) associations with six SNPs: a nonsynonymous variant in RPAP1, which is predicted to be damaging, three intronic SNPs (SEC24C, CASC17 and UQCC1) and two intergenic SNPs near to LY86 and FGF10. eQTL analyses found evidence for regulation of gene expression at three signals and implicated several genes including TYRO3 and PLAU. Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

genetics↗