scholarly journals Genome-wide polygenic score to identify a monogenic risk-equivalent for coronary disease

2017 ◽  
Author(s):  
Amit V. Khera ◽  
Mark Chaffin ◽  
Krishna G. Aragam ◽  
Connor A. Emdin ◽  
Derek Klarin ◽  
...  
Keyword(s):  
Coronary Disease ◽  
Fold Increase ◽  
Predictive Capacity ◽  
Cumulative Impact ◽  
Polygenic Score ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Polygenic Scores ◽  
Artery Disease

AbstractIdentification of individuals at increased genetic risk for a complex disorder such as coronary disease can facilitate treatments or enhanced screening strategies. A rare monogenic mutation associated with increased cholesterol is present in ~1:250 carriers and confers an up to 4-fold increase in coronary risk when compared with non-carriers. Although individual common polymorphisms have modest predictive capacity, their cumulative impact can be aggregated into a polygenic score. Here, we develop a new, genome-wide polygenic score that aggregates information from 6.6 million common polymorphisms and show that this score can similarly identify individuals with a 4-fold increased risk for coronary disease. In >400,000 participants from UK Biobank, the score conforms to a normal distribution and those in the top 2.5% of the distribution are at 4-fold increased risk compared to the remaining 97.5%. Similar patterns are observed with genome-wide polygenic scores for two additional diseases – breast cancer and severe obesity.One Sentence SummaryA genome-wide polygenic score identifies 2.5% of the population born with a 4-fold increased risk for coronary artery disease.

scholarly journals Validation of a Genome-Wide Polygenic Score for Coronary Artery Disease in South Asians

2020 ◽  
Vol 76 (6) ◽  
pp. 703-714 ◽  
Author(s):  
Minxian Wang ◽  
Ramesh Menon ◽  
Sanghamitra Mishra ◽  
Aniruddh P. Patel ◽  
Mark Chaffin ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
South Asians ◽  
Polygenic Score ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease

scholarly journals Association of Genetic Variation at AQP4 Locus with Vascular Depression

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 164 ◽  
Author(s):  
Anna L. Westermair ◽  
Matthias Munz ◽  
Anja Schaich ◽  
Stefan Nitsche ◽  
Bastian Willenborg ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Linkage Disequilibrium Block ◽  
Clinical Importance ◽  
In Silico Analysis ◽  
Fold Increase ◽  
Population Based ◽  
Vascular Depression ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease

Despite its substantial clinical importance, specific genetic variants associated with depression have not yet been identified. We sought to identify genetic variants associated with depression by (a) focusing on a more homogenous subsample (vascular depression) and (b) applying a three-stage approach. First, we contacted 730 participants with a confirmed atherosclerotic disease (coronary artery disease) from a population-based study population (German Myocardial Infarction Family Study IV) for psychiatric assessment with the Mini International Neuropsychiatric Interview. Second, we genotyped these patients using genome-wide single nucleotide polymorphism (SNP) arrays. Third, we characterized the SNP via in-silico analysis. The final sample consisted of 342 patients (78.3% male, age = 63.2 ± 9.9 years), 22.8% with a severe depressive disorder. Variant rs528732638 on chromosome 18q11.2 was a genome-wide significant variant and was associated with 3.6-fold increase in the odds of lifetime depression. The locus belongs to a linkage disequilibrium block showing expression quantitative trait loci effects on three putative cis-regulated genes, including the aquaporin 4 (AQP4) locus. AQP4 is already known to mediate the formation of ischemic edema in the brain and heart, increasing the size and extent of resulting lesions. Our findings indicate that AQP4 may also play a role in the etiopathology of vascular depression.

scholarly journals Discovery Of 42 Genome-Wide Significant Loci Associated With Dyslexia

2021 ◽  
Author(s):  
Catherine Doust ◽  
Pierre Fontanillas ◽  
Else Eising ◽  
Scott D Gordon ◽  
Zhengjun Wang ◽  
...  
Keyword(s):  
Genome Wide Association Study ◽  
Fold Increase ◽  
European Ancestry ◽  
Modern Life ◽  
Genetic Covariance ◽  
Hyperactivity Disorder ◽  
Genome Wide ◽  
A Genome ◽  
Polygenic Scores ◽  
Study Power

Reading and writing are crucial for many aspects of modern life but up to 1 in 10 children are affected by dyslexia, which can persist into adulthood. Family studies of dyslexia suggest heritability up to 70%, yet no convincing genetic markers have been found due to limited study power. Here, we present a genome-wide association study representing a 20-fold increase in sample size from prior work, with 51,800 adults self-reporting a dyslexia diagnosis and 1,087,070 controls. We identified 42 independent genome-wide significant loci: 17 are in genes linked to or pleiotropic with cognitive ability/educational attainment; 25 are novel and may be more specifically associated with dyslexia. Twenty-three loci (12 novel) were validated in independent cohorts of Chinese and European ancestry. We confirmed a similar genetic aetiology of dyslexia between sexes, and found genetic covariance with many traits, including ambidexterity, but not neuroanatomical measures of language-related circuitry. Causal analyses revealed a directional effect of dyslexia on attention deficit hyperactivity disorder and bidirectional effects on socio-educational traits but these relationships require further investigation. Dyslexia polygenic scores explained up to 6% of variance in reading traits in independent cohorts, and might in future enable earlier identification and remediation of dyslexia.

scholarly journals Transethnic Transferability of a Genome-wide Polygenic Score for Coronary Artery Disease

2020 ◽  
Author(s):  
Akl C. Fahed ◽  
Krishna G. Aragam ◽  
George Hindy ◽  
Yii-Der Ida Chen ◽  
Kumardeep Chaudhary ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Polygenic Score ◽  
Genome Wide ◽  
A Genome ◽  
Artery Disease

scholarly journals Clinical Relevance of Genome-Wide Polygenic Score may Be Less than Claimed

2018 ◽  
Author(s):  
David Curtis
Keyword(s):  
Threshold Model ◽  
Genome Wide ◽  
Increased Risk ◽  
Polygenic Scores ◽  
Cast Doubt ◽  
Inflammatory Bowel ◽  
Artery Disease ◽  
Risk Equivalent ◽  
Cad Risk ◽  
Operator Curve

A recent study claimed that genome-wide polygenic scores (GPSs) for five common diseases could identify individuals with risk equivalent to monogenic mutations. Receiver operator curve analyses were reported to have areas under the curve (AUCs) ranging from 0.63 for inflammatory bowel disease up to 0.81 for coronary artery disease (CAD). The GPS for CAD identified 8% of the population at threefold increased risk, which it was claimed was comparable to the excess risk from monogenic mutations. Attempts were made to model the distribution of GPS for CAD to match the information provided. Models were based on the reported distribution of prevalence and GPS and were fitted to the reported results using linear approximations to the distributions and using simulations of a liability-threshold model. It was impossible to produce a compatible model which produced an AUC as high as 0.81 and the most plausible estimate was that the true AUC was only 0.65. The reported distributions in cases and controls largely overlap so that they are not compatible with an AUC of 0.7 or more. The true AUC of the GPS for these diseases is much lower than claimed. Furthermore, the literature robustly demonstrates that true CAD risk associated with monogenic mutations is much higher than the threefold increase which was claimed. Together, these findings cast doubt on the clinical utility of the GPS.

scholarly journals Clinical Relevance of Genome-Wide Polygenic Score may Be Less than Claimed

2018 ◽  
Author(s):  
David Curtis
Keyword(s):  
Threshold Model ◽  
Genome Wide ◽  
Increased Risk ◽  
Polygenic Scores ◽  
Cast Doubt ◽  
Inflammatory Bowel ◽  
Artery Disease ◽  
Risk Equivalent ◽  
Cad Risk ◽  
Operator Curve

A recent study claimed that genome-wide polygenic scores (GPSs) for five common diseases could identify individuals with risk equivalent to monogenic mutations. Receiver operator curve analyses were reported to have areas under the curve (AUCs) ranging from 0.63 for inflammatory bowel disease up to 0.81 for coronary artery disease (CAD). The GPS for CAD identified 8% of the population at threefold increased risk, which it was claimed was comparable to the excess risk from monogenic mutations. Attempts were made to model the distribution of GPS for CAD to match the information provided. Models were based on the reported distribution of prevalence and GPS and were fitted to the reported results using linear approximations to the distributions and using simulations of a liability-threshold model. It was impossible to produce a compatible model which produced an AUC as high as 0.81 and the most plausible estimate was that the true AUC was only 0.65. The reported distributions in cases and controls largely overlap so that they are not compatible with an AUC of 0.7 or more. The true AUC of the GPS for these diseases is much lower than claimed. Furthermore, the literature robustly demonstrates that true CAD risk associated with monogenic mutations is much higher than the threefold increase which was claimed. Together, these findings cast doubt on the clinical utility of the GPS.

scholarly journals Clinical Relevance of Genome-Wide Polygenic Score may Be Less than Claimed

2018 ◽  
Author(s):  
David Curtis
Keyword(s):  
Threshold Model ◽  
Genome Wide ◽  
Increased Risk ◽  
Polygenic Scores ◽  
Cast Doubt ◽  
Inflammatory Bowel ◽  
Artery Disease ◽  
Risk Equivalent ◽  
Cad Risk ◽  
Operator Curve

A recent study claimed that genome-wide polygenic scores (GPSs) for five common diseases could identify individuals with risk equivalent to monogenic mutations. Receiver operator curve analyses were reported to have areas under the curve (AUCs) ranging from 0.63 for inflammatory bowel disease up to 0.81 for coronary artery disease (CAD) but these models also included age and sex, themselves strong predictors of risk. The GPS for CAD identified 8% of the population at threefold increased risk, which it was claimed was comparable to the excess risk from monogenic mutations. In the present study attempts were made to model the distribution of the GPS for CAD to match the information provided. These models were based on the reported distribution of prevalence by centile of GPS and on the distribution of GPS in controls and cases and were fitted to the reported results using linear approximations to the distributions and using simulations of a liability-threshold model. It was impossible to produce a compatible model in which the GPS produced an AUC as high as 0.81 and the most plausible estimate was that the true AUC was only 0.65. The reported distributions of the GPS in cases and controls overlap so much that they are not compatible with an AUC of 0.7 or higher. The AUC of the GPS for these diseases is modest. Furthermore, the literature robustly demonstrates that true CAD risk associated with monogenic mutations is much higher than the threefold increase which is predicted by the GPS. Together, these findings cast doubt on the clinical utility of the GPS.

scholarly journals The Genetic Basis of Hypertriglyceridemia

2021 ◽  
Vol 23 (8) ◽  
Author(s):  
Germán D. Carrasquilla ◽  
Malene Revsbech Christiansen ◽  
Tuomas O. Kilpeläinen
Keyword(s):  
Genetic Basis ◽  
Association Studies ◽  
Cumulative Effect ◽  
Genome Wide Association Studies ◽  
Genetic Loci ◽  
Risk Variants ◽  
Genome Wide ◽  
Severe Hypertriglyceridemia ◽  
Increased Risk ◽  
Polygenic Scores

Abstract Purpose of Review Hypertriglyceridemia is a common dyslipidemia associated with an increased risk of cardiovascular disease and pancreatitis. Severe hypertriglyceridemia may sometimes be a monogenic condition. However, in the vast majority of patients, hypertriglyceridemia is due to the cumulative effect of multiple genetic risk variants along with lifestyle factors, medications, and disease conditions that elevate triglyceride levels. In this review, we will summarize recent progress in the understanding of the genetic basis of hypertriglyceridemia. Recent Findings More than 300 genetic loci have been identified for association with triglyceride levels in large genome-wide association studies. Studies combining the loci into polygenic scores have demonstrated that some hypertriglyceridemia phenotypes previously attributed to monogenic inheritance have a polygenic basis. The new genetic discoveries have opened avenues for the development of more effective triglyceride-lowering treatments and raised interest towards genetic screening and tailored treatments against hypertriglyceridemia. Summary The discovery of multiple genetic loci associated with elevated triglyceride levels has led to improved understanding of the genetic basis of hypertriglyceridemia and opened new translational opportunities.

scholarly journals The FAM171A2 gene is a key regulator of progranulin expression and modifies the risk of multiple neurodegenerative diseases

2020 ◽  
Vol 6 (43) ◽  
pp. eabb3063
Author(s):  
Wei Xu ◽  
Si-Da Han ◽  
Can Zhang ◽  
Jie-Qiong Li ◽  
Yan-Jiang Wang ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Genome Wide Association Study ◽  
In Vitro Study ◽  
Genome Wide ◽  
A Genome ◽  
Increased Risk ◽  
Pathophysiological Role ◽  
Independent Cohort

Progranulin (PGRN) is a secreted pleiotropic glycoprotein associated with the development of common neurodegenerative diseases. Understanding the pathophysiological role of PGRN may help uncover biological underpinnings. We performed a genome-wide association study to determine the genetic regulators of cerebrospinal fluid (CSF) PGRN levels. Common variants in region of FAM171A2 were associated with lower CSF PGRN levels (rs708384, P = 3.95 × 10−12). This was replicated in another independent cohort. The rs708384 was associated with increased risk of Alzheimer’s disease, Parkinson’s disease, and frontotemporal dementia and could modify the expression of the FAM171A2 gene. FAM171A2 was considerably expressed in the vascular endothelium and microglia, which are rich in PGRN. The in vitro study further confirmed that the rs708384 mutation up-regulated the expression of FAM171A2, which caused a decrease in the PGRN level. Collectively, genetic, molecular, and bioinformatic findings suggested that FAM171A2 is a key player in regulating PGRN production.

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