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Cold Spring Harbor Perspectives in... Feb 2021Many exposures considered in Mendelian randomization (MR) studies are polygenic in that they are influenced by thousands of genetic variants. By using many... (Review)
Review
Many exposures considered in Mendelian randomization (MR) studies are polygenic in that they are influenced by thousands of genetic variants. By using many single-nucleotide polymorphisms (SNPs) as instrumental variables, more variation in the exposure is explained, increasing the precision of MR. Furthermore, methods can be designed that relax the assumptions of MR, especially concerning direct pleiotropic effects on the outcome. This article reviews the concepts and assumptions underlying the commonly used polygenic MR methods. Using a polygenic score as an instrument is equivalent to a weighted mean of individual SNP results, and the other fundamental averages, median and mode, may also be used to estimate causal effects. Outlier detection is useful for identifying pleiotropic SNPs to be excluded from analysis. Bayesian approaches are available to incorporate prior beliefs about pleiotropy. These methods each entail different assumptions, and together provide a set of sensitivity analyses to help triangulate evidence about causality.
Topics: Causality; Genetic Variation; Genome-Wide Association Study; Humans; Mendelian Randomization Analysis; Multifactorial Inheritance; Polymorphism, Single Nucleotide
PubMed: 32229610
DOI: 10.1101/cshperspect.a039586 -
Genome Biology Jun 2022Genetic studies of human traits have revolutionized our understanding of the variation between individuals, and yet, the genetics of most traits is still poorly... (Review)
Review
Genetic studies of human traits have revolutionized our understanding of the variation between individuals, and yet, the genetics of most traits is still poorly understood. In this review, we highlight the major open problems that need to be solved, and by discussing these challenges provide a primer to the field. We cover general issues such as population structure, epistasis and gene-environment interactions, data-related issues such as ancestry diversity and rare genetic variants, and specific challenges related to heritability estimates, genetic association studies, and polygenic risk scores. We emphasize the interconnectedness of these problems and suggest promising avenues to address them.
Topics: Gene-Environment Interaction; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide
PubMed: 35725481
DOI: 10.1186/s13059-022-02697-9 -
Cell Sep 2019The genetic architecture of autism spectrum disorder (ASD) is itself a diverse allelic spectrum that consists of rare de novo or inherited variants in hundreds of genes... (Review)
Review
The genetic architecture of autism spectrum disorder (ASD) is itself a diverse allelic spectrum that consists of rare de novo or inherited variants in hundreds of genes and common polygenic risk at thousands of loci. ASD susceptibility genes are interconnected at the level of transcriptional and protein networks, and many function as genetic regulators of neurodevelopment or synaptic proteins that regulate neural activity. So that the core underlying neuropathologies can be further elucidated, we emphasize the importance of first defining subtypes of ASD on the basis of the phenotypic signatures of genes in model systems and humans.
Topics: Animals; Autism Spectrum Disorder; Cells, Cultured; DNA Copy Number Variations; Disease Models, Animal; Gene Regulatory Networks; Genetic Predisposition to Disease; Humans; Multifactorial Inheritance; Neurogenesis
PubMed: 31491383
DOI: 10.1016/j.cell.2019.07.037 -
Molecular Psychiatry Jan 2022During the past decade, polygenic scores have become a fast-growing area of research in the behavioural sciences. The ability to directly assess people's genetic... (Review)
Review
During the past decade, polygenic scores have become a fast-growing area of research in the behavioural sciences. The ability to directly assess people's genetic propensities has transformed research by making it possible to add genetic predictors of traits to any study. The value of polygenic scores in the behavioural sciences rests on using inherited DNA differences to predict, from birth, common disorders and complex traits in unrelated individuals in the population. This predictive power of polygenic scores does not require knowing anything about the processes that lie between genes and behaviour. It also does not mandate disentangling the extent to which the prediction is due to assortative mating, genotype-environment correlation, or even population stratification. Although bottom-up explanation from genes to brain to behaviour will remain the long-term goal of the behavioural sciences, prediction is also a worthy achievement because it has immediate practical utility for identifying individuals at risk and is the necessary first step towards explanation. A high priority for research must be to increase the predictive power of polygenic scores to be able to use them as an early warning system to prevent problems.
Topics: Brain; Genome-Wide Association Study; Genotype; Humans; Multifactorial Inheritance; Phenotype
PubMed: 34686768
DOI: 10.1038/s41380-021-01348-y -
Nature Communications Dec 2023Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and...
Chronic kidney disease (CKD) is determined by an interplay of monogenic, polygenic, and environmental risks. Autosomal dominant polycystic kidney disease (ADPKD) and COL4A-associated nephropathy (COL4A-AN) represent the most common forms of monogenic kidney diseases. These disorders have incomplete penetrance and variable expressivity, and we hypothesize that polygenic factors explain some of this variability. By combining SNP array, exome/genome sequence, and electronic health record data from the UK Biobank and All-of-Us cohorts, we demonstrate that the genome-wide polygenic score (GPS) significantly predicts CKD among ADPKD monogenic variant carriers. Compared to the middle tertile of the GPS for noncarriers, ADPKD variant carriers in the top tertile have a 54-fold increased risk of CKD, while ADPKD variant carriers in the bottom tertile have only a 3-fold increased risk of CKD. Similarly, the GPS significantly predicts CKD in COL4A-AN carriers. The carriers in the top tertile of the GPS have a 2.5-fold higher risk of CKD, while the risk for carriers in the bottom tertile is not different from the average population risk. These results suggest that accounting for polygenic risk improves risk stratification in monogenic kidney disease.
Topics: Humans; Penetrance; Polycystic Kidney, Autosomal Dominant; Renal Insufficiency, Chronic; Multifactorial Inheritance; Risk Factors
PubMed: 38097619
DOI: 10.1038/s41467-023-43878-9 -
Pigment Cell & Melanoma Research Jan 2020Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Genome-wide linkage studies and genome-wide... (Review)
Review
Vitiligo is an autoimmune disease in which destruction of skin melanocytes results in patches of white skin and hair. Genome-wide linkage studies and genome-wide association studies in European ancestry cases identified over 50 vitiligo susceptibility loci, defining a model of melanocyte-directed autoimmunity. Vitiligo heritability is exceedingly high, ~2/3 coming from common and ~1/3 from rare genomic variants; ~20% of vitiligo risk is environmental. Vitiligo genetic risk is polygenic, with greater additive risk in multiplex vitiligo families than simplex cases. Vitiligo age-of-onset is bimodal, also involving a major genetic component; a MHC enhancer haplotype confers extreme risk for vitiligo (OR 8.1) and early disease onset, increasing expression of HLA-DQB1 mRNA and HLA-DQ protein and thus perhaps facilitating presentation of triggering antigens. Vitiligo triggering also involves a major environmental component; dramatic delay in vitiligo age-of-onset, especially from 1973 to 2004, suggests that exposure or response to a key vitiligo environmental trigger diminished during this period. Together, these findings provide deep understanding of vitiligo pathogenesis and genetic architecture, suggesting that vitiligo represents a tractable model for investigating complex disease genetic architecture and predictive aspects of personalized medicine.
Topics: Age of Onset; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Risk Factors; Vitiligo
PubMed: 31743585
DOI: 10.1111/pcmr.12848 -
PloS One 2022The variable presentations and different phenotypes of sepsis suggest that risk of sepsis comes from many genes each having a small effect. The cumulative effect can be...
BACKGROUND
The variable presentations and different phenotypes of sepsis suggest that risk of sepsis comes from many genes each having a small effect. The cumulative effect can be used to create individual risk profile. The purpose of this study was to create a polygenic risk score and determine the genetic variants associated with sepsis.
METHODS
We sequenced ~14 million single nucleotide polymorphisms with a minimac imputation quality R2>0.3 and minor allele frequency >10-6 in patients with Sepsis-2 or Sepsis-3. Genome-wide association was performed using Firth bias-corrected logistic regression. Semi-parsimonious logistic regression was used to create polygenic risk scores and reduced regression to determine the genetic variants independently associated with sepsis.
FINDINGS
2261 patients had sepsis and 13,068 control patients did not. The polygenic risk scores had good discrimination: c-statistic = 0.752 ± 0.005 for Sepsis-2 and 0.752 ± 0.007 for Sepsis-3. We found 772 genetic variants associated with Sepsis-2 and 442 with Sepsis-3, p<0.01. After multivariate adjustment, 100 variants on 85 genes were associated with Sepsis-2 and 69 variants in 54 genes with Sepsis-3. Twenty-five variants were present in both the Sepsis-2 and Sepsis-3 groups out of 32 genes that were present in both groups. The other 7 genes had different variants present. Most variants had small effect sizes.
CONCLUSIONS
Sepsis-2 and Sepsis-3 have both separate and shared genetic variants. Most genetic variants have small effects sizes, but cumulatively, the polygenic risk scores have good discrimination.
Topics: Gene Frequency; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Multifactorial Inheritance; Phenotype; Polymorphism, Single Nucleotide; Sepsis
PubMed: 35275946
DOI: 10.1371/journal.pone.0265052 -
European Journal of Epidemiology Sep 2023Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the...
Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the associations between higher levels of PA and better aerobic fitness and a lower risk for CMDs. We aimed to study how PA genotype associates with self-reported PA, aerobic fitness, cardiometabolic risk factors and diseases. PA genotype, which combined variation in over one million of gene variants, was composed using the SBayesR polygenic scoring methodology. First, we constructed a polygenic risk score for PA in the Trøndelag Health Study (N = 47,148) using UK Biobank single nucleotide polymorphism-specific weights (N = 400,124). The associations of the PA PRS and continuous variables were analysed using linear regression models and with CMD incidences using Cox proportional hazard models. The results showed that genotypes predisposing to higher amount of PA were associated with greater self-reported PA (Beta [B] = 0.282 MET-h/wk per SD of PRS for PA, 95% confidence interval [CI] = 0.211, 0.354) but not with aerobic fitness. These genotypes were also associated with healthier cardiometabolic profile (waist circumference [B = -0.003 cm, 95% CI = -0.004, -0.002], body mass index [B = -0.002 kg/m, 95% CI = -0.004, -0.001], high-density lipoprotein cholesterol [B = 0.004 mmol/L, 95% CI = 0.002, 0.006]) and lower incidence of hypertensive diseases (Hazard Ratio [HR] = 0.97, 95% CI = 0.951, 0.990), stroke (HR = 0.94, 95% CI = 0.903, 0.978) and type 2 diabetes (HR = 0.94, 95 % CI = 0.902, 0.970). Observed associations were independent of self-reported PA. These results support earlier findings suggesting small pleiotropic effects between PA and CMDs and provide new evidence about associations of polygenic inheritance of PA and intermediate cardiometabolic risk factors.
Topics: Humans; Cardiometabolic Risk Factors; Diabetes Mellitus, Type 2; Exercise; Hypertension; Multifactorial Inheritance; Genetic Risk Score
PubMed: 37603226
DOI: 10.1007/s10654-023-01029-w -
Neurobiology of Disease Aug 2020In this paper we explore the phenomenon of pleiotropy in neurodegenerative diseases, focusing on Alzheimer's disease (AD). We summarize the various techniques developed... (Review)
Review
In this paper we explore the phenomenon of pleiotropy in neurodegenerative diseases, focusing on Alzheimer's disease (AD). We summarize the various techniques developed to investigate pleiotropy among traits, elaborating in the polygenic risk scores (PRS) analysis. PRS was designed to assess a cumulative effect of a large number of SNPs for association with a disease and, later for disease risk prediction. Since genetic predictions rely on heritability, we discuss SNP-based heritability from genome-wide association studies and its contribution to the prediction accuracy of PRS. We review work examining pleiotropy in neurodegenerative diseases and related phenotypes and biomarkers. We conclude that the exploitation of pleiotropy may aid in the identification of novel genes and provide further insights in the disease mechanisms, and along with PRS analysis, may be advantageous for precision medicine.
Topics: Genetic Pleiotropy; Genetic Predisposition to Disease; Humans; Multifactorial Inheritance; Neurodegenerative Diseases; Polymorphism, Single Nucleotide
PubMed: 32445791
DOI: 10.1016/j.nbd.2020.104953 -
Biological Psychiatry Jan 2021Genome-wide analyses of common and rare genetic variations have documented the heritability of major psychiatric disorders, established their highly polygenic genetic... (Review)
Review
Genome-wide analyses of common and rare genetic variations have documented the heritability of major psychiatric disorders, established their highly polygenic genetic architecture, and identified hundreds of contributing variants. In recent years, these studies have illuminated another key feature of the genetic basis of psychiatric disorders: the important role and pervasive nature of pleiotropy. It is now clear that a substantial fraction of genetic influences on psychopathology transcend clinical diagnostic boundaries. In this review, we summarize evidence in psychiatry for pleiotropy at multiple levels of analysis: from overall genome-wide correlation to biological pathways and down to the level of individual loci. We examine underlying mechanisms of observed pleiotropy, including genetic effects on neurodevelopment, diverse actions of regulatory elements, mediated effects, and spurious associations of genomic variation with multiple phenotypes. We conclude with an exploration of the implications of pleiotropy for understanding the genetic basis of psychiatric disorders, informing nosology, and advancing the aims of precision psychiatry and genomic medicine.
Topics: Genetic Predisposition to Disease; Genome-Wide Association Study; Genomics; Humans; Mental Disorders; Multifactorial Inheritance; Phenotype
PubMed: 33131714
DOI: 10.1016/j.biopsych.2020.09.026