Biology subjects

Montasser, M. E.

Publications and source records attributed to Montasser, M. E..

6 recordsLinked to original sources

bioRxiv2025

Metabolomics Ex/GWAS in the Amish reveals novel insights into cardiometabolic disease pathways

We conducted an exome and genome-wide association study (Ex/GWAS) of 1,015 metabolites in serum samples from 5,981 Amish adults. We identified 149 functional or likely functional genetic variants, based on CADD scores significantly associated (P < 5.8 x 10-8) with 519 metabolite levels, 69 of which were >10-fold enriched in the Amish versus Europeans in gnomAD. We discovered novel associations involving a PCK2 splice-donor variant (rs138881435) and metabolites important for energy metabolism and mitochondrial function. In UK Biobank participants, this variant was associated with increased longitudinal relaxation time (T1) values on liver MRI suggesting increased inflammation and fibrosis. Furthermore, we found novel associations involving ENPEP stop-gain variant (rs33966350) and peptide and amino acid metabolite levels, implicating ENPEPs roles in blood pressure regulation. Additional known and novel genetic variant-metabolite associations were identified including genes involved in Amish-enriched Mendelian diseases and cardiometabolic traits, providing insights into underlying mechanisms of these disorders.

genomics↗

bioRxiv2025

Whole blood transcriptional signatures of age and survival identified in Long Life Family and Integrative Longevity Omics Studies

Although aging is a universal event, some individuals are able to achieve extreme longevity. The Long-Life Family Study (LLFS) enrolls participants from families enriched with long-lived individuals, serves as a valuable dataset for studying ageing phenotypes and identify potential intervention targets. We analyzed the association between age at blood draw and 16,284 RNAseq-based blood transcriptomic data from 2,167 LLFS participants with ages ranging from 18 to 107, replicated the results in the Integrative Longevity Omics Study (ILO) dataset of 20,884 RNAseq-based blood transcriptomic data from 419 participants, with ages ranging from 60 to 108, and further compared our findings to a published reference aging signature. We identified 4,227 transcripts increasing and 4,044 transcripts decreasing with age, and enrichment analysis revealed age-related upregulation of inflammatory and senescence-related pathways, and downregulation of MYC and Wnt/{beta}-catenin targets, among others. Further, a subset of transcripts showed age associations unique to the longevity-enriched cohorts (LLFS and ILO). We also identified 314 transcripts significantly associated with mortality risk and found that pro-survival gene sets included NK cell-mediated cytotoxicity and GPCR signaling. Finally, increased transcriptomic age predicted using transcriptomic clock was strongly associated with increased mortality. In summary, this study identified robust transcriptomic signatures of aging and mortality in a longevity-enriched population, highlighting key biological pathways such as immune modulation, inflammation, and senescence. Authors notesThis manuscript has been peer-reviewed and accepted by GeroScience (Springer). This bioRxiv article reflects the published version, incorporating revisions made in response to reviewers comments. The main content, results, and conclusions remain unchanged from the previous version, while the Discussion section has been expanded to further address the functional annotation and clinical relevance of the identified markers. Copy of the acceptance letterThe editors are pleased to inform you that your manuscript, JAAA-D-25-01946R1 entitled "Whole blood transcriptional signatures of age and survival identified in Long Life Family and Integrative Longevity Omics Studies" has been accepted for publication in GeroScience as an Original Article. The editors commend you on your outstanding contribution to the journal. Your manuscript can be published online ahead of print within approximately two weeks.

molecular biology↗

bioRxiv2021

Whole genome sequence analysis of blood lipid levels in >66,000 individuals

Plasma lipids are heritable modifiable causal factors for coronary artery disease, the leading cause of death globally. Despite the well-described monogenic and polygenic bases of dyslipidemia, limitations remain in discovery of lipid-associated alleles using whole genome sequencing, partly due to limited sample sizes, ancestral diversity, and interpretation of potential clinical significance. Increasingly larger whole genome sequence datasets with plasma lipids coupled with methodologic advances enable us to more fully catalog the allelic spectrum for lipids. Here, among 66,329 ancestrally diverse (56% non-European ancestry) participants, we associate 428M variants from deep-coverage whole genome sequences with plasma lipids. Approximately 400M of these variants were not studied in prior lipids genetic analyses. We find multiple lipid-related genes strongly associated with plasma lipids through analysis of common and rare coding variants. We additionally discover several significantly associated rare non-coding variants largely at Mendelian lipid genes. Notably, we detect rare LDLR intronic variants associated with markedly increased LDL-C, similar to rare LDLR exonic variants. In conclusion, we conducted a systematic whole genome scan for plasma lipids expanding the alleles linked to lipids for multiple ancestries and characterize a clinically-relevant rare non-coding variant model for lipids.

genetics↗

bioRxiv2021

Leveraging a founder population to identify novel rare-population genetic determinants of lipidome

Identifying the genetic determinants of inter-individual variation in lipid species (lipidome) may provide deeper understanding and new insight into the mechanistic effect of complex lipidomic pathways in CVD risk and progression beyond simple traditional lipids. Previous studies have been largely population based and thus only powered to discover associations with common genetic variants. Founder populations represent a powerful resource to accelerate discovery of novel biology associated with rare population alleles that have risen to higher frequency due to genetic drift. We performed a GWAS of 355 lipid species in 650 individuals from the Old Order Amish founder population including 127 lipid species not previously tested. We report for the first time the lipid species associated with two rare-population but Amish-enriched lipid variants: APOB_rs5742904 and APOC3_rs76353203. We also identified novel associations for 3 rare-population Amish-enriched loci with several sphingolipids and with proposed potential functional/causal variant in each locus including GLPTD2_rs536055318, CERS5_rs771033566, and AKNA_rs531892793. We replicated 7 previously known common loci including novel associations with two sterols: androstenediol with UGT locus on chromosome 2 and estriol with SLC22A8/A24 locus on chromosome 11. Our results show the power of founder populations to discover novel biology due to genetic drift that can increase the frequency of an allele from only few copies in large sample cohorts such as the UK Biobank to dozens of copies in sample size as small as 650.

genetics↗

bioRxiv2020

Robust, flexible, and scalable tests for Hardy-Weinberg Equilibrium across diverse ancestries

Traditional Hardy-Weinberg equilibrium (HWE) tests (the {chi}2 test and the exact test) have long been used as a metric for evaluating genotype quality, as technical artifacts leading to incorrect genotype calls often can be identified as deviations from HWE. However, in datasets comprised of individuals from diverse ancestries, HWE can be violated even without genotyping error, complicating the use of HWE testing to assess genotype data quality. In this manuscript, we present the Robust Unified Test for HWE (RUTH) to test for HWE while accounting for population structure and genotype uncertainty, and evaluate the impact of population heterogeneity and genotype uncertainty on the standard HWE tests and alternative methods using simulated and real sequence datasets. Our results demonstrate that ignoring population structure or genotype uncertainty in HWE tests can inflate false positive rates by many orders of magnitude. Our evaluations demonstrate different tradeoffs between false positives and statistical power across the methods, with RUTH consistently amongst the best across all evaluations. RUTH is implemented as a practical and scalable software tool to rapidly perform HWE tests across millions of markers and hundreds of thousands of individuals while supporting standard VCF/BCF formats. RUTH is publicly available at https://www.github.com/statgen/ruth.

bioinformatics↗

bioRxiv2019

Genetic and functional evidence relates a missense variant in B4GALT1 to lower LDL-C and fibrinogen

Increased LDL-cholesterol (LDL-C) and fibrinogen are independent risk factors for cardiovascular disease (CVD). We identified novel associations between an Amish-enriched missense variant (p.Asn352Ser) in a functional domain of beta-1,4-galactosyltransferase 1 (B4GALT1) and 13.5 mg/dl lower LDL-C (p=1.6E-15), and 26 mg/dl lower plasma fibrinogen (p= 9.8E-05). N-linked glycan profiling found p.Asn352Ser to be associated (p-values from 1.4E-06 to 1.0E-17) with decreased glycosylation of glycoproteins including: fibrinogen, ApoB100, immunoglobulin G (IgG), and transferrin. In vitro assays found that the mutant (352Ser) protein had 50% lower galactosyltransferase activity compared to wild type (352Asn) protein. Knockdown of b4galt1 in zebrafish embryos resulted in significantly lower LDL-C compared to control, which was fully rescued by co-expression of 352Asn human B4GALT1 mRNA but only partially rescued by co-expression of 352Ser human B4GALT1 mRNA. Our findings establish B4GALT1 as a novel gene associated with lower LDL-C and fibrinogen and suggest that targeted modulation of protein glycosylation may represent a therapeutic approach to decrease CVD risk.

genetics↗