Thrombotic risk determined by protein C receptor (PROCR) variants among middle-aged and older adults: a population-based cohort study

2022 ◽  
Author(s):  
Eric Manderstedt ◽  
Christer Hallden ◽  
Christina Lind-Hallden ◽  
Johan Elf ◽  
peter svensson ◽  
...  
Keyword(s):  
Older Adults ◽  
Protein C ◽  
Association Studies ◽  
Large Population ◽  
Missense Variant ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Middle Aged ◽  
Thrombotic Risk

Background: The protein C (PC) anticoagulant system has a key role in maintaining hemostatic balance. One missense (Ser219Gly) variant in the protein C receptor (PROCR) was associated with venous thromboembolism (VTE) in genome-wide association studies. Objectives: This study aimed to determine the thrombotic risk of rare and common PROCR variants in a large population-based cohort of middle-aged and older adults. Patients/Methods: The exonic sequence of PROCR was analyzed for the Ser219Gly variant and other qualifying variants in 28,794 subjects (born 1923-1950, 60% women) without previous VTE, who participated in the Malmö Diet and Cancer study (1991-1996). Incidence of VTE was followed up until 2018. Qualifying variants were defined as loss-of-function or non-benign (PolyPhen-2) missense variants with minor allele frequencies (MAF) < 0.1%. Results: Resequencing identified 36 PROCR variants in the study population (26,210 non-VTE exomes and 2584 VTE exomes), 11 synonymous, 22 missense and three loss-of-function variants. Kaplan-Meier analysis of the known Ser219Gly variant (rs867186) showed that homozygosity for this variant increased the risk of disease whereas heterozygosity showed no effect. Cox multivariate regression analysis revealed an adjusted hazard ratio of 1.5 (95%CI 1.1-2.0). Fifteen rare variants were classified as qualifying and were included in collapsing analysis (burden test and SKAT-O). They did not contribute to risk. However, a Arg113Cys missense variant (rs146420040; MAF=0.004) showed an increased VTE risk (HR=1.3; 95%CI 1.0-1.9). Conclusions: Homozygosity for the Ser219Gly variant and a previously identified functional PROCR variant (Arg113Cys) was associated with VTE. Other variants did not contribute to VTE.

scholarly journals GWAS of serum ALT and AST reveals an association of SLC30A10 Thr95Ile with hypermanganesemia symptoms

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Lucas D. Ward ◽  
Ho-Chou Tu ◽  
Chelsea B. Quenneville ◽  
Shira Tsour ◽  
Alexander O. Flynn-Carroll ◽  
...  
Keyword(s):  
Bile Duct ◽  
Extrahepatic Bile Duct ◽  
Association Studies ◽  
Missense Variant ◽  
Deficiency Anemia ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Extrahepatic Bile Duct Cancer ◽  
Hepatocellular Damage ◽  
Increased Risk

AbstractUnderstanding mechanisms of hepatocellular damage may lead to new treatments for liver disease, and genome-wide association studies (GWAS) of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum activities have proven useful for investigating liver biology. Here we report 100 loci associating with both enzymes, using GWAS across 411,048 subjects in the UK Biobank. The rare missense variant SLC30A10 Thr95Ile (rs188273166) associates with the largest elevation of both enzymes, and this association replicates in the DiscovEHR study. SLC30A10 excretes manganese from the liver to the bile duct, and rare homozygous loss of function causes the syndrome hypermanganesemia with dystonia-1 (HMNDYT1) which involves cirrhosis. Consistent with hematological symptoms of hypermanganesemia, SLC30A10 Thr95Ile carriers have increased hematocrit and risk of iron deficiency anemia. Carriers also have increased risk of extrahepatic bile duct cancer. These results suggest that genetic variation in SLC30A10 adversely affects more individuals than patients with diagnosed HMNDYT1.

scholarly journals Sleep patterns and insomnia in a large population‐based study of middle‐aged and older adults: The Tromsø study 2015–2016

2020 ◽  
Author(s):  
Børge Sivertsen ◽  
Ståle Pallesen ◽  
Oddgeir Friborg ◽  
Kristian Bernhard Nilsen ◽  
Øystein Kvåle Bakke ◽  
...  
Keyword(s):  
Older Adults ◽  
Large Population ◽  
Population Based ◽  
Middle Aged ◽  
Sleep Patterns ◽  
Population Based Study

Self-perceived coping resources of middle-aged and older adults – results of a large population-based study

2016 ◽  
Vol 21 (12) ◽  
pp. 1303-1309 ◽  
Author(s):  
Friederike H. Boehlen ◽  
Wolfgang Herzog ◽  
Dieter Schellberg ◽  
Imad Maatouk ◽  
Kai-Uwe Saum ◽  
...  
Keyword(s):  
Older Adults ◽  
Large Population ◽  
Population Based ◽  
Coping Resources ◽  
Middle Aged ◽  
Population Based Study

scholarly journals Phenotypic and genetic markers of psychopathology in a population-based sample of older adults

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Arianna M. Gard ◽  
Erin B. Ware ◽  
Luke W. Hyde ◽  
Lauren L. Schmitz ◽  
Jessica Faul ◽  
...  
Keyword(s):  
Older Adults ◽  
Large Population ◽  
The United States ◽  
Population Based ◽  
European Ancestry ◽  
Equation Modeling ◽  
General Factor ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Polygenic Scores

AbstractAlthough psychiatric phenotypes are hypothesized to organize into a two-factor internalizing–externalizing structure, few studies have evaluated the structure of psychopathology in older adults, nor explored whether genome-wide polygenic scores (PGSs) are associated with psychopathology in a domain-specific manner. We used data from 6003 individuals of European ancestry from the Health and Retirement Study, a large population-based sample of older adults in the United States. Confirmatory factor analyses were applied to validated measures of psychopathology and PGSs were derived from well-powered genome-wide association studies (GWAS). Genomic SEM was implemented to construct latent PGSs for internalizing, externalizing, and general psychopathology. Phenotypically, the data were best characterized by a single general factor of psychopathology, a factor structure that was replicated across genders and age groups. Although externalizing PGSs (cannabis use, antisocial behavior, alcohol dependence, attention deficit hyperactivity disorder) were not associated with any phenotypes, PGSs for major depressive disorder, neuroticism, and anxiety disorders were associated with both internalizing and externalizing phenotypes. Moreover, the variance explained in the general factor of psychopathology increased by twofold (from 1% to 2%) using the latent internalizing or latent one-factor PGSs, derived using weights from Genomic Structural Equation Modeling (SEM), compared with any of the individual PGSs. Collectively, results suggest that genetic risk factors for and phenotypic markers of psychiatric disorders are transdiagnostic in older adults of European ancestry. Alternative explanations are discussed, including methodological limitations of GWAS and phenotypic measurement of psychiatric outcome in large-scale population-based studies.

Candidate Genes for Nonsyndromic Cleft Palate Detected by Exome Sequencing

2017 ◽  
Vol 96 (11) ◽  
pp. 1314-1321 ◽  
Author(s):  
A.K. Hoebel ◽  
D. Drichel ◽  
M. van de Vorst ◽  
A.C. Böhmer ◽  
S. Sivalingam ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Rare Variants ◽  
Association Studies ◽  
Low Frequency ◽  
Missense Variant ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Novel Variant

Nonsyndromic cleft palate only (nsCPO) is a facial malformation that has a livebirth prevalence of 1 in 2,500. Research suggests that the etiology of nsCPO is multifactorial, with a clear genetic component. To date, genome-wide association studies have identified only 1 conclusive common variant for nsCPO, that is, a missense variant in the gene grainyhead-like-3 ( GRHL3). Thus, the underlying genetic causes of nsCPO remain largely unknown. The present study aimed at identifying rare variants that might contribute to nsCPO risk, via whole-exome sequencing (WES), in multiply affected Central European nsCPO pedigrees. WES was performed in 2 affected first-degree relatives from each family. Variants shared between both individuals were analyzed for their potential deleterious nature and a low frequency in the general population. Genes carrying promising variants were annotated for 1) reported associations with facial development, 2) multiple occurrence of variants, and 3) expression in mouse embryonic palatal shelves. This strategy resulted in the identification of a set of 26 candidate genes that were resequenced in 132 independent nsCPO cases and 623 independent controls of 2 different ethnicities, using molecular inversion probes. No rare loss-of-function mutation was identified in either WES or resequencing step. However, we identified 2 or more missense variants predicted to be deleterious in each of 3 genes ( ACACB, PTPRS, MIB1) in individuals from independent families. In addition, the analyses identified a novel variant in GRHL3 in 1 patient and a variant in CREBBP in 2 siblings. Both genes underlie different syndromic forms of CPO. A plausible hypothesis is that the apparently nonsyndromic clefts in these 3 patients might represent hypomorphic forms of the respective syndromes. In summary, the present study identified rare variants that might contribute to nsCPO risk and suggests candidate genes for further investigation.

Genetics of Hypertension

2018 ◽  
Author(s):  
Matthew A. Sparks ◽  
Paul J Phelan
Keyword(s):  
Association Studies ◽  
Large Population ◽  
Antihypertensive Agents ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Monogenic Diseases ◽  
High Prevalence ◽  
Shared Risk

Despite the high prevalence of hypertension and its resulting morbidity and mortality, our knowledge of its pathogenesis remains limited. Strong evidence for a genetic role in blood pressure (BP) variability was first provided by familial segregation studies and the identification of mendelian disorders causing marked hypertension. These monogenic diseases, largely involving genes in sodium homeostatic pathways, have reinforced the Guytonian principle that BP is largely governed by renal sodium excretion. More recently, large population based genome wide association studies (GWAS) have attempted to fill in the missing heritability of the BP trait, with mixed results. Although many variants have been identified that are robustly associated with BP variability, they are mostly rare and together are responsible for a tiny percentage of total trait variability. Observations from GWAS include shared risk variants for cardiovascular and kidney disease, including polymorphisms in UMOD. Mutations in this gene are known to cause monogenic renal disease. GWAS data may be employed for pathway analysis to discover the etiology of hypertension as well providing the potential to interrogate drug responses to antihypertensive agents depending on genotype. The chapter concludes with describing future directions in BP genetics including evidence of the role of epigenetic mechanisms in BP pathogenesis. As we enter the era of whole genome sequencing, the possibility exists to discover the missing hereditability of BP variation although this technology will present its own challenges. This review contains 6 figures, 2 tables and 94 references Key words: adrenocorticotropic hormone, autosomal dominant,  autosomal recessive, cytosine-phosphate-guanine, epithelial sodium channel

scholarly journals Genetic and lifestyle risk factors for MRI-defined brain infarcts in a population-based setting

Neurology ◽  
2019 ◽  
Vol 92 (5) ◽  
pp. e486-e503 ◽  
Author(s):  
Ganesh Chauhan ◽  
Hieab H.H. Adams ◽  
Claudia L. Satizabal ◽  
Joshua C. Bis ◽  
Alexander Teumer ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Risk ◽  
Association Studies ◽  
Large Population ◽  
Population Based ◽  
Genome Wide Association Studies ◽  
Lifestyle Risk Factors ◽  
Brain Infarcts ◽  
Genome Wide ◽  
Lifestyle Risk

ObjectiveTo explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts.MethodsWe performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n = 20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI.ResultsThe mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10−8; and LINC00539/ZDHHC20, p = 5.82 × 10−9. Both have been associated with blood pressure (BP)–related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10−25; p[SSBI] = 5.23 × 10−14 for hypertension), smoking (p[BI] = 4.4 × 10−10; p[SSBI] = 1.2 × 10−4), diabetes (p[BI] = 1.7 × 10−8; p[SSBI] = 2.8 × 10−3), previous cardiovascular disease (p[BI] = 1.0 × 10−18; p[SSBI] = 2.3 × 10−7), stroke (p[BI] = 3.9 × 10−69; p[SSBI] = 3.2 × 10−24), and MRI-defined white matter hyperintensity burden (p[BI] = 1.43 × 10−157; p[SSBI] = 3.16 × 10−106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p ≤ 0.0022), without indication of directional pleiotropy.ConclusionIn this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

scholarly journals Schizophrenia-associated SLC39A8 polymorphism is a loss-of-function allele altering glutamate receptor and innate immune signaling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Wei Chou Tseng ◽  
Veronica Reinhart ◽  
Thomas A. Lanz ◽  
Mark L. Weber ◽  
Jincheng Pang ◽  
...  
Keyword(s):  
Association Studies ◽  
Missense Variant ◽  
Synaptic Cleft ◽  
Surface Expression ◽  
Genome Wide Association Studies ◽  
Zinc Transport ◽  
Loss Of Function ◽  
Glutamate Signaling ◽  
Inflammatory Signals ◽  
The Impact

AbstractSchizophrenia is a complex and heterogenous disease that presents with abnormalities in glutamate signaling and altered immune and inflammatory signals. Genome-wide association studies have indicated specific genes and pathways that may contribute to schizophrenia. We assessed the impact of the functional missense variant SLC39A8 (ZIP8)-A391T (ZIP8A391T) on zinc transport, glutamate signaling, and the neuroinflammatory response. The ZIP8A391T mutation resulted in reduced zinc transport into the cell, suggesting a loss in the tight control of zinc in the synaptic cleft. Electrophysiological recordings from perturbed neurons revealed a significant reduction in NMDA- and AMPA-mediated spontaneous EPSCs (sEPSCs) and a reduction in GluN2A and GluA1/2/3 receptor surface expression. All phenotypes were rescued by re-expression of wild-type ZIP8 (ZIP8WT) or application of the membrane-impermeable zinc chelator ZX1. ZIP8 reduction also resulted in decreased BBB integrity, increased IL-6/IL-1β protein expression, and increased NFκB following TNFα stimulation, indicating that ZIP8 loss-of-function may exacerbate immune and inflammatory signals. Together, our findings demonstrate that the A391T missense mutation results in alterations in glutamate and immune function and provide novel therapeutic targets relevant to schizophrenia.

scholarly journals The genetic structure of the Turkish population reveals high levels of variation and admixture

2021 ◽  
Vol 118 (36) ◽  
pp. e2026076118
Author(s):  
M. Ece Kars ◽  
A. Nazlı Başak ◽  
O. Emre Onat ◽  
Kaya Bilguvar ◽  
Jungmin Choi ◽  
...  
Keyword(s):  
Genetic Structure ◽  
Association Studies ◽  
Middle Eastern ◽  
Turkish Population ◽  
Population Based ◽  
Genotype Imputation ◽  
Genome Wide Association Studies ◽  
Inherited Disease ◽  
Loss Of Function ◽  
Inbreeding Coefficients

The construction of population-based variomes has contributed substantially to our understanding of the genetic basis of human inherited disease. Here, we investigated the genetic structure of Turkey from 3,362 unrelated subjects whose whole exomes (n = 2,589) or whole genomes (n = 773) were sequenced to generate a Turkish (TR) Variome that should serve to facilitate disease gene discovery in Turkey. Consistent with the history of present-day Turkey as a crossroads between Europe and Asia, we found extensive admixture between Balkan, Caucasus, Middle Eastern, and European populations with a closer genetic relationship of the TR population to Europeans than hitherto appreciated. We determined that 50% of TR individuals had high inbreeding coefficients (≥0.0156) with runs of homozygosity longer than 4 Mb being found exclusively in the TR population when compared to 1000 Genomes Project populations. We also found that 28% of exome and 49% of genome variants in the very rare range (allele frequency < 0.005) are unique to the modern TR population. We annotated these variants based on their functional consequences to establish a TR Variome containing alleles of potential medical relevance, a repository of homozygous loss-of-function variants and a TR reference panel for genotype imputation using high-quality haplotypes, to facilitate genome-wide association studies. In addition to providing information on the genetic structure of the modern TR population, these data provide an invaluable resource for future studies to identify variants that are associated with specific phenotypes as well as establishing the phenotypic consequences of mutations in specific genes.

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