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.

scholarly journals Phenotypic and Genetic Markers of Psychopathology in a Population-Based Sample of Older Adults

2019 ◽  
Author(s):  
Arianna M. Gard ◽  
Erin B. Ware ◽  
Luke W. Hyde ◽  
Lauren Schmitz ◽  
Jessica Faul ◽  
...  
Keyword(s):  
Older Adults ◽  
Psychiatric Disorders ◽  
Large Population ◽  
Age Groups ◽  
The United States ◽  
Population Based ◽  
European Ancestry ◽  
General Factor ◽  
Confirmatory Factor Analyses ◽  
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 6,216 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 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, ADHD) were not associated with any phenotypes, PGSs for MDD, neuroticism, and anxiety disorders were associated with both internalizing and externalizing phenotypes. Moreover, the latent internalizing PGS and the latent one-factor PGS, derived using weights from Genomic SEM, explained 1% more variance in the general factor of psychopathology than any of the individual PGSs. Results support the following conclusions: genetic risk factors for and phenotypic markers of psychiatric disorders are transdiagnostic in European ancestries, GWAS-derived PGSs fail to capture genetic variation associated with disease specificity in European ancestries, and blunt phenotypic measurement in GWAS may preclude our ability to evaluate the structure and specificity of genetic contributions to psychiatric disorders.

scholarly journals Linkage disequilibrium maps for European and African populations constructed from whole genome sequence data

2019 ◽  
Vol 6 (1) ◽  
Author(s):  
Alejandra Vergara-Lope ◽  
M. Reza Jabalameli ◽  
Clare Horscroft ◽  
Sarah Ennis ◽  
Andrew Collins ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Genome Sequence ◽  
Sequence Data ◽  
Association Studies ◽  
Large Population ◽  
Whole Genome Sequence ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Whole Genome ◽  
Genome Wide

Abstract Quantification of linkage disequilibrium (LD) patterns in the human genome is essential for genome-wide association studies, selection signature mapping and studies of recombination. Whole genome sequence (WGS) data provides optimal source data for this quantification as it is free from biases introduced by the design of array genotyping platforms. The Malécot-Morton model of LD allows the creation of a cumulative map for each choromosome, analogous to an LD form of a linkage map. Here we report LD maps generated from WGS data for a large population of European ancestry, as well as populations of Baganda, Ethiopian and Zulu ancestry. We achieve high average genetic marker densities of 2.3–4.6/kb. These maps show good agreement with prior, low resolution maps and are consistent between populations. Files are provided in BED format to allow researchers to readily utilise this resource.

scholarly journals Pan-Cancer Study Detects Novel Genetic Risk Variants and Shared Genetic Basis in Two Large Cohorts

2019 ◽  
Author(s):  
Sara R. Rashkin ◽  
Rebecca E. Graff ◽  
Linda Kachuri ◽  
Khanh K. Thai ◽  
Stacey E. Alexeeff ◽  
...  
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Large Population ◽  
Regulatory Elements ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Risk Variants ◽  
Genome Wide ◽  
Pan Cancer ◽  
Shared Genetic

AbstractDeciphering the shared genetic basis of distinct cancers has the potential to elucidate carcinogenic mechanisms and inform broadly applicable risk assessment efforts. However, no studies have investigated pan-cancer pleiotropy within single, well-defined populations unselected for phenotype. We undertook novel genome-wide association studies (GWAS) and comprehensive evaluations of heritability and pleiotropy across 18 cancer types in two large, population-based cohorts: the UK Biobank (413,870 European ancestry individuals; 48,961 cancer cases) and the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohorts (66,526 European ancestry individuals; 16,001 cancer cases). The GWAS detected 21 novel genome-wide significant risk variants. In addition, numerous cancer sites exhibited clear heritability. Investigations of pleiotropy identified 12 cancer pairs exhibiting either positive or negative genetic correlations and 43 pleiotropic loci. We identified 158 pleiotropic variants, many of which were enriched for regulatory elements and influenced cross-tissue gene expression. Our findings demonstrate widespread pleiotropy and offer further insight into the complex genetic architecture of cross-cancer susceptibility.

scholarly journals An integrated personal and population-based Egyptian genome reference

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Inken Wohlers ◽  
Axel Künstner ◽  
Matthias Munz ◽  
Michael Olbrich ◽  
Anke Fähnrich ◽  
...  
Keyword(s):  
Genetic Variation ◽  
De Novo ◽  
Disease Risk ◽  
Population Based ◽  
European Ancestry ◽  
Whole Genome Sequencing Data ◽  
Sequencing Data ◽  
Human Genomes ◽  
Genome Wide ◽  
Polygenic Scores

Abstract A small number of de novo assembled human genomes have been reported to date, and few have been complemented with population-based genetic variation, which is particularly important for North Africa, a region underrepresented in current genome-wide references. Here, we combine long- and short-read whole-genome sequencing data with recent assembly approaches into a de novo assembly of an Egyptian genome. The assembly demonstrates well-balanced quality metrics and is complemented with variant phasing via linked reads into haploblocks, which we associate with gene expression changes in blood. To construct an Egyptian genome reference, we identify genome-wide genetic variation within a cohort of 110 Egyptian individuals. We show that differences in allele frequencies and linkage disequilibrium between Egyptians and Europeans may compromise the transferability of European ancestry-based genetic disease risk and polygenic scores, substantiating the need for multi-ethnic genome references. Thus, the Egyptian genome reference will be a valuable resource for precision medicine.

scholarly journals Polygenic predictors of age-related decline in cognitive ability

2019 ◽  
Vol 25 (10) ◽  
pp. 2584-2598 ◽  
Author(s):  
Stuart J. Ritchie ◽  
W. David Hill ◽  
Riccardo E. Marioni ◽  
Gail Davies ◽  
Saskia P. Hagenaars ◽  
...  
Keyword(s):  
Cognitive Ability ◽  
Association Studies ◽  
Cognitive Change ◽  
Genome Wide Association ◽  
General Factor ◽  
Genome Wide Association Studies ◽  
Cognitive Ageing ◽  
Health Lifestyle ◽  
Genome Wide ◽  
Polygenic Scores

AbstractPolygenic scores can be used to distil the knowledge gained in genome-wide association studies for prediction of health, lifestyle, and psychological factors in independent samples. In this preregistered study, we used fourteen polygenic scores to predict variation in cognitive ability level at age 70, and cognitive change from age 70 to age 79, in the longitudinal Lothian Birth Cohort 1936 study. The polygenic scores were created for phenotypes that have been suggested as risk or protective factors for cognitive ageing. Cognitive abilities within older age were indexed using a latent general factor estimated from thirteen varied cognitive tests taken at four waves, each three years apart (initialn = 1091 age 70; finaln = 550 age 79). The general factor indexed over two-thirds of the variance in longitudinal cognitive change. We ran additional analyses using an age-11 intelligence test to index cognitive change from age 11 to age 70. Several polygenic scores were associated with the level of cognitive ability at age-70 baseline (range of standardizedβ-values = –0.178 to 0.302), and the polygenic score for education was associated with cognitive change from childhood to age 70 (standardizedβ = 0.100). No polygenic scores were statistically significantly associated with variation in cognitive change between ages 70 and 79, and effect sizes were small. However,APOEe4 status made a significant prediction of the rate of cognitive decline from age 70 to 79 (standardizedβ = –0.319 for carriers vs. non-carriers). The results suggest that the predictive validity for cognitive ageing of polygenic scores derived from genome-wide association study summary statistics is not yet on a par withAPOEe4, a better-established predictor.

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 Theoretical and empirical quantification of the accuracy of polygenic scores in ancestry divergent populations

2020 ◽  
Author(s):  
Ying Wang ◽  
Jing Guo ◽  
Guiyan Ni ◽  
Jian Yang ◽  
Peter M. Visscher ◽  
...  
Keyword(s):  
Complex Traits ◽  
Association Studies ◽  
African Ancestry ◽  
Real Data ◽  
European Ancestry ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Polygenic Scores ◽  
Causal Variants ◽  
The Uk

AbstractPolygenic scores (PGS) have been widely used to predict complex traits and risk of diseases using variants identified from genome-wide association studies (GWASs). To date, most GWASs have been conducted in populations of European ancestry, which limits the use of GWAS-derived PGS in non-European populations. Here, we develop a new theory to predict the relative accuracy (RA, relative to the accuracy in populations of the same ancestry as the discovery population) of PGS across ancestries. We used simulations and real data from the UK Biobank to evaluate our results. We found across various simulation scenarios that the RA of PGS based on trait-associated SNPs can be predicted accurately from modelling linkage disequilibrium (LD), minor allele frequencies (MAF), cross-population correlations of SNP effect sizes and heritability. Altogether, we find that LD and MAF differences between ancestries explain alone up to ~70% of the loss of RA using European-based PGS in African ancestry for traits like body mass index and height. Our results suggest that causal variants underlying common genetic variation identified in European ancestry GWASs are mostly shared across continents.

Genetics of Sleep and Insights into Its Relationship with Obesity

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Hassan S. Dashti ◽  
José M. Ordovás
Keyword(s):  
Sleep Disorders ◽  
Healthy Lifestyle ◽  
Association Studies ◽  
Genetic Correlations ◽  
European Ancestry ◽  
Annual Review ◽  
Publication Date ◽  
Genome Wide Association Studies ◽  
Genome Wide ◽  
Polygenic Scores

Considerable recent advancements in elucidating the genetic architecture of sleep traits and sleep disorders may provide insight into the relationship between sleep and obesity. Despite the considerable involvement of the circadian clock in sleep and metabolism, few shared genes, including FTO, were implicated in genome-wide association studies (GWASs) of sleep and obesity. Polygenic scores composed of signals from GWASs of sleep traits show largely null associations with obesity, suggesting lead variants are unique to sleep. Modest genome-wide genetic correlations are observed between many sleep traits and obesity and are largest for snoring.Notably, U-shaped positive genetic correlations with body mass index (BMI) exist for both short and long sleep durations. Findings from Mendelian randomization suggest robust causal effects of insomnia on higher BMI and, conversely, of higher BMI on snoring and daytime sleepiness. Bidirectional effects between sleep duration and daytime napping with obesity may also exist. Limited gene-sleep interaction studies suggest that achieving favorable sleep, as part of a healthy lifestyle, may attenuate genetic predisposition to obesity, but whether these improvements produce clinically meaningful reductions in obesity risk remains unclear. Investigations of the genetic link between sleep and obesity for sleep disorders other than insomnia and in populations of non-European ancestry are currently limited. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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

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