👤 Mohsen Ghanbari

BackgroundIdentifying genetic variants conferring resilience to Alzheimer's disease and related dementia (ADRD) may hold promise for developing therapeutics.ObjectiveTo determine genetic associations with being dementia-free at age 85 (DF85).MethodsWe examined genetic associations, using whole genome sequencing data, with DF85 in three Trans-Omics for Precision Medicine cohorts and the Alzheimer's Disease Sequencing Project Phenotype Harmonization Consortium. We tested common variants individually and aggregation of rare (MAF ≤ 1%) coding and non-coding variants in DF85 participants (n = 3657) against individuals who were not DF85 (n = 20,010). We verified associations using a stricter control set who developed dementia before age 85 (n = 5552).ResultsWe observed an association at Show less

The MetaboHealth score is an indicator of physiological frailty in middle aged and older individuals. The aim of the current study was to explore which molecular pathways co-vary with the MetaboHealth score. Using a Luminex cytokine assay and liquid chromatography-mass spectrometry-based proteomics we explored the plasma proteins associating with the difference in 100 extreme scoring individuals selected from two large population cohorts, the Leiden Longevity Study (LLS) and the Rotterdam Study (RS), and discordant monozygotic twin pairs from the Netherlands Twin Register (NTR). In addition, we estimated the heritability of the score using 726 monozygotic (MZ) and 450 dizygotic (DZ) twin pairs. In the contrasting extreme scoring individuals from LLS and RS, we uncovered significant differences in 3 (out of 15) cytokines (GDF15, IL6, and MIG), and 106 (out of 289) plasma proteins. The high, poor health related, score associated with 42 increased inflammatory and immune related protein levels (CRP, LBP, HPT) and lowered levels of 71 HDL remodeling and cholesterol transport related proteins (e.g. APOA1, APOA2, APOA4, and TETN). Using the NTR twins, we subsequently showed that the MetaboHealth score is moderately heritable (h Show less

Refractive error (RE) and myopia are complex polygenic conditions with the majority of genome-wide associated genetic variants in non-exonic regions. Given this, and the onset during childhood, gene-regulation is expected to play an important role in its pathogenesis. This prompted us to explore beyond traditional gene finding approaches. We performed a genetic association study between variants in non-coding RNAs and enhancers, and RE and myopia. We obtained single-nucleotide polymorphisms (SNPs) in microRNA (miRNA) genes, miRNA-binding sites, long non-coding RNAs genes (lncRNAs) and enhancers from publicly available databases: miRNASNPv2, PolymiRTS, VISTA Enhancer Browser, FANTOM5 and lncRNASNP2. We investigated whether SNPs overlapping these elements were associated with RE and myopia leveraged from a large GWAS meta-analysis (N = 160,420). With genetic risk scores (GRSs) per element, we investigated the joint effect of associated variants on RE, axial length (AL)/corneal radius (CR), and AL progression in an independent child cohort, the Generation R Study (N = 3638 children). We constructed a score for biological plausibility per SNP in highly confident miRNA-binding sites and enhancers in chromatin accessible regions. We found that SNPs in two miRNA genes, 14 enhancers and 81 lncRNA genes in chromatin accessible regions and 54 highly confident miRNA-binding sites, were in RE and myopia-associated loci. GRSs from SNPs in enhancers were significantly associated with RE, AL/CR and AL progression. GRSs from lncRNAs were significantly associated with all AL/CR and AL progression. GRSs from miRNAs were not associated with any ocular biometric measurement. GRSs from miRNA-binding sites showed suggestive but inconsistent significance. We prioritized candidate miRNA binding sites and candidate enhancers for future functional validation. Pathways of target and host genes of highly ranked variants included eye development (BMP4, MPPED2), neurogenesis (DDIT4, NTM), extracellular matrix (ANTXR2, BMP3), photoreceptor metabolism (DNAJB12), photoreceptor morphogenesis (CHDR1), neural signaling (VIPR2) and TGF-beta signaling (ANAPC16). This is the first large-scale study of non-coding RNAs and enhancers for RE and myopia. Enhancers and lncRNAs could be of large importance as they are associated with childhood myopia. We provide a confident blueprint for future functional validation by prioritizing candidate miRNA binding sites and candidate enhancers. Show less

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression. Perturbations in plasma miRNA levels are known to impact disease risk and have potential as disease biomarkers. Exploring the genetic regulation of miRNAs may yield new insights into their important role in governing gene expression and disease mechanisms. We present genome-wide association studies of 2083 plasma circulating miRNAs in 2178 participants of the Rotterdam Study to identify miRNA-expression quantitative trait loci (miR-eQTLs). We identify 3292 associations between 1289 SNPs and 63 miRNAs, of which 65% are replicated in two independent cohorts. We demonstrate that plasma miR-eQTLs co-localise with gene expression, protein, and metabolite-QTLs, which help in identifying miRNA-regulated pathways. We investigate consequences of alteration in circulating miRNA levels on a wide range of clinical conditions in phenome-wide association studies and Mendelian randomisation using the UK Biobank data (N = 423,419), revealing the pleiotropic and causal effects of several miRNAs on various clinical conditions. In the Mendelian randomisation analysis, we find a protective causal effect of miR-1908-5p on the risk of benign colon neoplasm and show that this effect is independent of its host gene (FADS1). This study enriches our understanding of the genetic architecture of plasma miRNAs and explores the signatures of miRNAs across a wide range of clinical conditions. The integration of population-based genomics, other omics layers, and clinical data presents opportunities to unravel potential clinical significance of miRNAs and provides tools for novel miRNA-based therapeutic target discovery. Show less

Migraine affects over a billion individuals worldwide but its genetic underpinning remains largely unknown. Here, we performed a genome-wide association study of 102,084 migraine cases and 771,257 controls and identified 123 loci, of which 86 are previously unknown. These loci provide an opportunity to evaluate shared and distinct genetic components in the two main migraine subtypes: migraine with aura and migraine without aura. Stratification of the risk loci using 29,679 cases with subtype information indicated three risk variants that seem specific for migraine with aura (in HMOX2, CACNA1A and MPPED2), two that seem specific for migraine without aura (near SPINK2 and near FECH) and nine that increase susceptibility for migraine regardless of subtype. The new risk loci include genes encoding recent migraine-specific drug targets, namely calcitonin gene-related peptide (CALCA/CALCB) and serotonin 1F receptor (HTR1F). Overall, genomic annotations among migraine-associated variants were enriched in both vascular and central nervous system tissue/cell types, supporting unequivocally that neurovascular mechanisms underlie migraine pathophysiology. Show less

The HERMES (HEart failure Molecular Epidemiology for Therapeutic targetS) consortium aims to identify the genomic and molecular basis of heart failure. The consortium currently includes 51 studies from 11 countries, including 68 157 heart failure cases and 949 888 controls, with data on heart failure events and prognosis. All studies collected biological samples and performed genome-wide genotyping of common genetic variants. The enrolment of subjects into participating studies ranged from 1948 to the present day, and the median follow-up following heart failure diagnosis ranged from 2 to 116 months. Forty-nine of 51 individual studies enrolled participants of both sexes; in these studies, participants with heart failure were predominantly male (34-90%). The mean age at diagnosis or ascertainment across all studies ranged from 54 to 84 years. Based on the aggregate sample, we estimated 80% power to genetic variant associations with risk of heart failure with an odds ratio of ≥1.10 for common variants (allele frequency ≥ 0.05) and ≥1.20 for low-frequency variants (allele frequency 0.01-0.05) at P < 5 × 10 HERMES is a global collaboration aiming to (i) identify the genetic determinants of heart failure; (ii) generate insights into the causal pathways leading to heart failure and enable genetic approaches to target prioritization; and (iii) develop genomic tools for disease stratification and risk prediction. Show less

ChREBP (carbohydrate responsive element binding protein) is a transcription factor that responds to sugar consumption. Sugar-sweetened beverage (SSB) consumption and genetic variants in the Data from 11 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (N=63 599) and the UK Biobank (N=59 220) were used to quantify associations of SSB consumption, genetic variants, and their interaction on HDL-C and triglyceride concentrations using linear regression models. A total of 1606 single nucleotide polymorphisms within or near In a meta-analysis, rs71556729 was significantly associated with higher HDL-C concentrations only among the highest SSB consumers (β, 2.12 [95% CI, 1.16-3.07] mg/dL per allele; Our results identified genetic variants in the Show less

Sex is a major determinant of cardiometabolic risk. DNA methylation (DNAm), an important epigenetic mechanism that differs between sexes, has been associated with cardiometabolic diseases. Therefore, we aimed to systematically review studies in adults investigating sex-specific associations of DNAm with intermediate cardiometabolic traits and incident cardiovascular disease including stroke, myocardial infarction (MI) and coronary heart disease (CHD). Five bibliographic databases were searched from inception to 15 July 2019. We selected 35 articles (based on 30 unique studies) from 17,023 references identified, with a total of 14,020 participants of European, North American or Asian ancestry. Four studies reported sex differences between global DNAm and blood lipid levels and stroke risk. In 25 studies that took a genome wide or candidate gene approach, DNAm at 31 gene sites was associated with sex differences in cardiometabolic diseases. The identified genes were PLA2G7, BCL11A, KDM6A, LIPC, ABCG1, PLTP, CETP, ADD1, CNN1B, HOOK2, GFBP-7,PTPN1, GCK, PTX3, ABCG1, GALNT2, CDKN2B, APOE, CTH, GNASAS, INS, PON1, TCN2, CBS, AMT, KDMA6A, FTO, MAP3K13, CCDC8, MMP-2 and ER-α. Prioritized pathway connectivity analysis associated these genes with biological pathways such as vitamin B12 metabolism, statin pathway, plasma lipoprotein, plasma lipoprotein assembly, remodeling and clearance and cholesterol metabolism. Our findings suggest that DNAm might be a promising molecular strategy for understanding sex differences in the pathophysiology of cardiometabolic diseases and that future studies should investigate the effects of sex on epigenetic mechanisms in cardiometabolic risk. In addition, we emphasize the gap between the translational potential and the clinical utilization of cardiometabolic epigenetics. Show less

Genome-wide association studies enabled us to discover a large number of variants and genomic loci contributing to cardiovascular and metabolic disorders. However, because the vast majority of the identified variants are thought to merely be proxies for other functional variants, the causal mechanisms remain to be elucidated. We hypothesized that the part of the functional variants involved in deregulating cardiometabolic genes is located in microRNA (miRNA)-binding sites. Using the largest genome-wide association studies available on glycemic indices, lipid traits, anthropometric measures, blood pressure, coronary artery diseases, and type 2 diabetes mellitus, we identified 11,067 variants that are associated with cardiometabolic phenotypes. Of these, 230 variants are located within miRNA-binding sites in the 3'-untranslated region of 155 cardiometabolic genes. Thirty-seven of 230 variants were found to fulfill our predefined criteria for being functional in their genomic loci. Ten variants were subsequently selected for experimental validation based on genome-wide association studies results, expression quantitative trait loci (eQTL) analyses, and coexpression of their host genes and regulatory miRNAs in relevant tissues. Luciferase reporter assays revealed an allele-specific regulation of genes hosting the variants by miRNAs. These cotransfection experiments showed that rs174545 (FADS1:miR-181a-2), rs1059611 (LPL:miR-136), rs13702 (LPL:miR-410), rs1046875 (FN3KRP:miR-34a), rs7956 (MKRN2:miR-154), rs3217992 (CDKN2B:miR-138-2-3p), and rs11735092 (HSD17B13:miR-375) decrease or abrogate miRNA-dependent regulation of the genes. Conversely, 2 variants, rs6857 (PVRL2:miR-320e) and rs907091 (IKZF3:miR-326), were shown to enhance the activity of miRNAs on their host genes. We provide evidence for a model in which polymorphisms in miRNA-binding sites can both positively and negatively affect miRNA-mediated regulation of cardiometabolic genes. Show less