GWAS on Birth Year Infant Mortality Rates Provides New Evidence of Recent Natural Selection

Following more than a century of phenotypic measurement of natural selection processes, much recent work explores relationships between molecular genetic measurements and realized fitness in the next generation. We take a novel approach to the study of contemporary selective pressure by examining which genetic variants are "sustained" in populations as mortality exposure declines. Specifically, we deploy a so-called "regional GWAS" that links the infant mortality rate (IMR) by place and year in the UK with common genetic variants among cohorts in the UK Biobank. These cohorts (born 1936-1970) saw a decline in IMR from above 65 per 1,000 to under 20 per 1,000, with substantial subnational variation and spikes alongside wartime exposures. Our results show several genome-wide significant loci, including LCT and TLR10/1/6, related to area-level cohort IMR exposure during gestation and infancy. Genetic correlations are found across multiple domains, including fertility, cognition, health behaviors, and health outcomes, suggesting an important role for cohort selection in modern populations.

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Genome-wide association study identifies 48 common genetic variants associated with handedness

10.1101/831321 ◽

2019 ◽

Author(s):

Gabriel Cuellar Partida ◽

Joyce Y Tung ◽

Nicholas Eriksson ◽

Eva Albrecht ◽

Fazil Aliev ◽

...

Keyword(s):

Association Study ◽

Genetic Variants ◽

Complex Traits ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Genome Wide Association ◽

Left Handedness ◽

Left Handed ◽

Genome Wide ◽

Common Genetic Variants

AbstractHandedness, a consistent asymmetry in skill or use of the hands, has been studied extensively because of its relationship with language and the over-representation of left-handers in some neurodevelopmental disorders. Using data from the UK Biobank, 23andMe and 32 studies from the International Handedness Consortium, we conducted the world’s largest genome-wide association study of handedness (1,534,836 right-handed, 194,198 (11.0%) left-handed and 37,637 (2.1%) ambidextrous individuals). We found 41 genetic loci associated with left-handedness and seven associated with ambidexterity at genome-wide levels of significance (P < 5×10−8). Tissue enrichment analysis implicated the central nervous system and brain tissues including the hippocampus and cerebrum in the etiology of left-handedness. Pathways including regulation of microtubules, neurogenesis, axonogenesis and hippocampus morphology were also highlighted. We found suggestive positive genetic correlations between being left-handed and some neuropsychiatric traits including schizophrenia and bipolar disorder. SNP heritability analyses indicated that additive genetic effects of genotyped variants explained 5.9% (95% CI = 5.8% – 6.0%) of the underlying liability of being left-handed, while the narrow sense heritability was estimated at 12% (95% CI = 7.2% – 17.7%). Further, we show that genetic correlation between left-handedness and ambidexterity is low (rg = 0.26; 95% CI = 0.08 – 0.43) implying that these traits are largely influenced by different genetic mechanisms. In conclusion, our findings suggest that handedness, like many other complex traits is highly polygenic, and that the genetic variants that predispose to left-handedness may underlie part of the association with some psychiatric disorders that has been observed in multiple observational studies.

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Integration of rare large-effect expression variants improves polygenic risk prediction

10.1101/2020.12.02.20242990 ◽

2020 ◽

Author(s):

Craig Smail ◽

Nicole M. Ferraro ◽

Matthew G. Durrant ◽

Abhiram S. Rao ◽

Matthew Aguirre ◽

...

Keyword(s):

Genetic Variants ◽

Rare Variants ◽

Complex Trait ◽

Risk Scores ◽

Multiple Traits ◽

Polygenic Risk ◽

Common Genetic Variants ◽

Using Data ◽

The Uk ◽

The Impact

SummaryPolygenic risk scores (PRS) aim to quantify the contribution of multiple genetic loci to an individual’s likelihood of a complex trait or disease. However, existing PRS estimate genetic liability using common genetic variants, excluding the impact of rare variants. We identified rare, large-effect variants in individuals with outlier gene expression from the GTEx project and then assessed their impact on PRS predictions in the UK Biobank (UKB). We observed large deviations from the PRS-predicted phenotypes for carriers of multiple outlier rare variants; for example, individuals classified as “low-risk” but in the top 1% of outlier rare variant burden had a 6-fold higher rate of severe obesity. We replicated these findings using data from the NHLBI Trans-Omics for Precision Medicine (TOPMed) biobank and the Million Veteran Program, and demonstrated that PRS across multiple traits will significantly benefit from the inclusion of rare genetic variants.

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Genetic and environmental contributions to psychological resilience and coping

Wellcome Open Research ◽

10.12688/wellcomeopenres.13854.1 ◽

2018 ◽

Vol 3 ◽

pp. 12 ◽

Cited By ~ 6

Author(s):

Lauren B Navrady ◽

Yanni Zeng ◽

Toni-Kim Clarke ◽

Mark J Adams ◽

David M Howard ◽

...

Keyword(s):

Genetic Variants ◽

Coping Style ◽

Genetic Correlations ◽

Genetic Effects ◽

Shared Environment ◽

Psychological Resilience ◽

Common Genetic Variants ◽

Family Based ◽

And Coping ◽

Shared Environments

Background: Twin studies indicate that genetic and environmental factors contribute to both psychological resilience and coping style, but estimates of their relative molecular and shared environmental contributions are limited. The degree of overlap in the genetic architectures of these traits is also unclear. Methods: Using data from a large population- and family-based cohort Generation Scotland (N = 8,734), we estimated the genetic and shared environmental variance components for resilience, task-, emotion-, and avoidance-oriented coping style in a linear mixed model (LMM). Bivariate LMM analyses were used to estimate the genetic correlations between these traits. Resilience and coping style were measured using the Brief Resilience Scale and Coping Inventory for Stressful Situations, respectively. Results: The greatest proportion of the phenotypic variance in resilience remained unexplained, although significant contributions from common genetic variants and family-shared environment were found. Both task- and avoidance-oriented coping had significant contributions from common genetic variants, sibling- and couple-shared environments, variance in emotion-oriented coping was attributable to common genetic variants, family- and couple-shared environments. The estimated correlation between resilience and emotion-oriented coping was high for both common-variant-associated genetic effects (rG = -0.79, se = 0.19), and for the additional genetic effects from the pedigree (rK = -0.94, se = 0.30). Genetic correlations between resilience and task- and avoidance-oriented coping did not meet statistical significance. Conclusions: Both genetics and shared environmental effects were major contributing factors to coping style, whilst the variance in resilience remains largely unexplained. Strong genetic overlap between resilience and emotion-oriented coping suggests a relationship whereby genetic factors that increase negative emotionality also lead to decreased resilience. We suggest that genome-wide family-based studies of resilience and coping may help to elucidate tractable methodologies to identify genetic architectures and modifiable environmental risk factors to protect against psychiatric illness, although further work with larger sample sizes is needed.

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Genetic analysis identifies molecular systems and biological pathways associated with household income

10.1101/573691 ◽

2019 ◽

Author(s):

W. David Hill ◽

Neil M. Davies ◽

Stuart J. Ritchie ◽

Nathan G. Skene ◽

Julien Bryois ◽

...

Keyword(s):

Cognitive Ability ◽

Genetic Variants ◽

Household Income ◽

Association Studies ◽

Genetic Correlations ◽

Functional Enrichment ◽

Genome Wide Association Studies ◽

Income Differences ◽

Genome Wide ◽

Common Genetic Variants

AbstractSocio-economic position (SEP) is a multi-dimensional construct reflecting (and influencing) multiple socio-cultural, physical, and environmental factors. Previous genome-wide association studies (GWAS) using household income as a marker of SEP have shown that common genetic variants account for 11% of its variation. Here, in a sample of 286,301 participants from UK Biobank, we identified 30 independent genome-wide significant loci, 29 novel, that are associated with household income. Using a recently-developed method to meta-analyze data that leverages power from genetically-correlated traits, we identified an additional 120 income-associated loci. These loci showed clear evidence of functional enrichment, with transcriptional differences identified across multiple cortical tissues, in addition to links with GABAergic and serotonergic neurotransmission. We identified neurogenesis and the components of the synapse as candidate biological systems that are linked with income. By combining our GWAS on income with data from eQTL studies and chromatin interactions, 24 genes were prioritized for follow up, 18 of which were previously associated with cognitive ability. Using Mendelian Randomization, we identified cognitive ability as one of the causal, partly-heritable phenotypes that bridges the gap between molecular genetic inheritance and phenotypic consequence in terms of income differences. Significant differences between genetic correlations indicated that, the genetic variants associated with income are related to better mental health than those linked to educational attainment (another commonly-used marker of SEP). Finally, we were able to predict 2.5% of income differences using genetic data alone in an independent sample. These results are important for understanding the observed socioeconomic inequalities in Great Britain today.

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Abstract 16685: Shared Genetic Pathways Contribute to Risk of Hypertrophic and Dilated Cardiomyopathies With Opposite Directions of Effect

Circulation ◽

10.1161/circ.142.suppl_3.16685 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Rafik Tadros ◽

Catherine Francis ◽

Xiao Xu ◽

Alexa M Vermeer ◽

Andrew R Harper ◽

...

Keyword(s):

Risk Score ◽

Genetic Variants ◽

Rare Variants ◽

Genetic Correlations ◽

Left Ventricular ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Clinical Events ◽

Mutation Carriers ◽

Common Genetic Variants

Introduction: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies are leading causes of sudden death and heart failure requiring transplantation in young individuals. While some cases have a monogenic underlying cause, the majority remain unexplained. Objective: To better understand the contribution of common genetic variants in susceptibility and severity of cardiomyopathy. Methods: We conducted three genome-wide association studies (GWAS) and multi-trait analyses in European-ancestry individuals, including a HCM (1,733 cases) and DCM meta-analyses (5,521 cases), and a GWAS of 9 left ventricular (LV) traits in 19,260 healthy participants from the UK Biobank that underwent cardiac magnetic resonance imaging. We investigated genetic correlations between LV traits, HCM and DCM using LD score regression. We used two-sample mendelian randomization (MR) to assess the causal relationship of increased LV contractility with HCM risk. Lastly, we derived a polygenic risk score and assessed whether it modulates maximal LV wall thickness (maxLVWT) and clinical events in 368 sarcomeric mutation carriers, using linear and Cox mixed effects models, respectively. Results: We identified 16 genetic loci (15 novel) associated with HCM, 13 loci (7 novel) associated with DCM, and 23 loci associated with LV traits. We showed strong genetic correlations between LV volumes and contractility traits in the general population and cardiomyopathies, with opposing effects in HCM and DCM. Using MR, we demonstrated a causal association linking increased LV contractility with HCM risk and estimated that each unit (1%) increase in LV ejection fraction increases the risk of HCM by 37% (95% CI 10%-69%, P=0.004). Lastly, a polygenic risk score (PRS HCM ) derived from the HCM GWAS was associated with maxLVWT (P=0.0001) and clinical events (P=0.009) in carriers of HCM-causing rare variants. Conclusion: Our findings highlight the contribution of common genetic variants in susceptibility for HCM and DCM, and in severity in sarcomeric mutation carriers. Our data also point to increased LV contractility as an important mechanism of HCM independently of sarcomere activating rare variants, and highlight the potential clinical relevance of PRS for risk stratification in HCM.

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Shared genetic etiology between anxiety disorders and psychiatric and related intermediate phenotypes

Psychological Medicine ◽

10.1017/s003329171900059x ◽

2019 ◽

Vol 50 (4) ◽

pp. 692-704 ◽

Cited By ~ 4

Author(s):

Kazutaka Ohi ◽

Takeshi Otowa ◽

Mihoko Shimada ◽

Tsukasa Sasaki ◽

Hisashi Tanii

Keyword(s):

Anxiety Disorders ◽

Psychiatric Disorders ◽

Genetic Variants ◽

Large Scale ◽

Genetic Correlations ◽

Well Being ◽

Subjective Well Being ◽

Intermediate Phenotypes ◽

Genome Wide ◽

Common Genetic Variants

AbstractBackgroundPsychiatric disorders and related intermediate phenotypes are highly heritable and have a complex, overlapping polygenic architecture. A large-scale genome-wide association study (GWAS) of anxiety disorders identified genetic variants that are significant on a genome-wide. The current study investigated the genetic etiological overlaps between anxiety disorders and frequently cooccurring psychiatric disorders and intermediate phenotypes.MethodsUsing case–control and factor score models, we investigated the genetic correlations of anxiety disorders with eight psychiatric disorders and intermediate phenotypes [the volumes of seven subcortical brain regions, childhood cognition, general cognitive ability and personality traits (subjective well-being, loneliness, neuroticism and extraversion)] from large-scale GWASs (n= 7556–298 420) by linkage disequilibrium score regression.ResultsAmong psychiatric disorders, the risk of anxiety disorders was positively genetically correlated with the risks of major depressive disorder (MDD) (rg± standard error = 0.83 ± 0.16,p= 1.97 × 10−7), schizophrenia (SCZ) (0.28 ± 0.09,p= 1.10 × 10−3) and attention-deficit/hyperactivity disorder (ADHD) (0.34 ± 0.13,p= 8.40 × 10−3). Among intermediate phenotypes, significant genetic correlations existed between the risk of anxiety disorders and neuroticism (0.81 ± 0.17,p= 1.30 × 10−6), subjective well-being (−0.73 ± 0.18,p= 4.89 × 10−5), general cognitive ability (−0.23 ± 0.08,p= 4.70 × 10−3) and putamen volume (−0.50 ± 0.18,p= 5.00 × 10−3). No other significant genetic correlations between anxiety disorders and psychiatric or intermediate phenotypes were observed (p> 0.05). The case–control model yielded stronger genetic effect sizes than the factor score model.ConclusionsOur findings suggest that common genetic variants underlying the risk of anxiety disorders contribute to elevated risks of MDD, SCZ, ADHD and neuroticism and reduced quality of life, putamen volume and cognitive performance. We suggest that the comorbidity of anxiety disorders is partly explained by common genetic variants.

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Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension

Cells ◽

10.3390/cells10030638 ◽

2021 ◽

Vol 10 (3) ◽

pp. 638

Author(s):

Shahood Fazal ◽

Malik Bisserier ◽

Lahouaria Hadri

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Right Ventricular ◽

Genetic Variants ◽

High Throughput Sequencing ◽

Molecular Genetic ◽

Pulmonary Arteries ◽

Pulmonary Vasculature ◽

Common Genetic Variants ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.

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Polygenic modulation of lipoprotein(a)-associated cardiovascular risk

10.1101/2020.02.22.20026757 ◽

2020 ◽

Author(s):

Mark Trinder ◽

Liam R. Brunham

Keyword(s):

Myocardial Infarction ◽

Cardiovascular Risk ◽

Genetic Variants ◽

Uk Biobank ◽

Lower Quintile ◽

Lipoprotein A ◽

Common Genetic Variants ◽

Artery Disease ◽

The Uk ◽

Genomic Risk

ABSTRACTAimsElevated levels of lipoprotein(a) are one of the strongest inherited risk factors for coronary artery disease (CAD). However, there is variability in cardiovascular risk among individuals with elevated lipoprotein(a). The sources of this variability are incompletely understood. We assessed the effects of a genomic risk score (GRS) for CAD on risk of myocardial infarction among individuals with elevated lipoprotein(a).MethodsWe calculated CAD GRSs for 408,896 individuals of British white ancestry from the UK Biobank using 6.27 million common genetic variants. Lipoprotein(a) levels were measured in 310,020 individuals. The prevalence and risk of myocardial infarction versus CAD GRS percentiles were compared for individuals with and without elevated lipoprotein(a) defined as ≥120 or 168 nmol/L (≈50 or 70 mg/dL, respectively).ResultsIndividuals with elevated lipoprotein(a) displayed significantly greater CAD GRSs than individuals without elevated lipoprotein(a), which was largely dependent on the influence of genetic variants within or near the LPA gene. Continuous levels of CAD GRS percentile were significantly associated with risk of myocardial infarction for individuals with elevated lipoprotein(a). Notably, the risk of myocardial infarction for males with elevated lipoprotein(a) levels, but a CAD GRS percentile in the lower quintile (<20th percentile), was less than the overall risk of myocardial infarction for males with non-elevated lipoprotein(a) levels (hazard ratio [95% CI]: 0.79 [0.64-0.97], p=0.02). Similar results were observed for females.ConclusionThese data suggest that CAD genomic scores influence cardiovascular risk among individuals with elevated lipoprotein(a) and may aid in identifying candidates for preventive therapies.

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Genetic Susceptibility to Pneumonia: A GWAS Meta-Analysis Between the UK Biobank and FinnGen

Twin Research and Human Genetics ◽

10.1017/thg.2021.27 ◽

2021 ◽

pp. 1-10

Author(s):

Adrian I. Campos ◽

Pik Kho ◽

Karla X. Vazquez-Prada ◽

Luis M. García-Marín ◽

Nicholas G. Martin ◽

...

Keyword(s):

Individual Differences ◽

Meta Analysis ◽

Genetic Correlations ◽

Sensitivity Analyses ◽

Smoking History ◽

Chromosome 15 ◽

Uk Biobank ◽

Common Genetic Variants ◽

Small Effect Size ◽

The Uk

Abstract Pneumonia is a respiratory condition with complex etiology. Host genetic variation is thought to contribute to individual differences in susceptibility and symptom manifestation. Here, we analyze pneumonia data from the UK Biobank (14,780 cases and 439,096 controls) and FinnGen (9980 cases and 86,519 controls) and perform a genomewide association study meta-analysis. We use gene-based tests, colocalization, genetic correlation, latent causal variable (LCV) and polygenic prediction in an independent Australian sample (N = 5595) to draw insights into the etiology of pneumonia risk. We identify two independent loci on chromosome 15 (lead single-nucleotide polymorphisms rs2009746 and rs76474922) to be associated with pneumonia (p < 5e−8). Gene-based tests revealed 18 genes in chromosomes 15, 16 and 9, including IL127, PBX3, ApoB receptor (APOBR) and smoking related genes CHRNA3/5, statistically associated with pneumonia. We observed genetic correlations between pneumonia and cardiorespiratory, psychiatric and inflammatory related traits. LCV analysis suggests a strong genetic causal relationship with cardiovascular health phenotypes. Polygenic risk scores for pneumonia significantly predicted self-reported pneumonia in an independent sample, albeit with a small effect size (OR = 1.11 95% CI [1.04, 1.19], p < .05). Sensitivity analyses suggested the associations in chromosome 15 are mediated by smoking history, but the associations in chromosomes 16 and 9, and polygenic prediction were robust to adjustment for smoking. Altogether, our results highlight common genetic variants, genes and potential pathways that contribute to individual differences in susceptibility to pneumonia, and advance our understanding of the genetic factors underlying heterogeneity in respiratory medical outcomes.

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Multifactorial disorders and polygenic risk scores: predicting common diseases and the possibility of adverse selection in life and protection insurance

Annals of Actuarial Science ◽

10.1017/s1748499520000226 ◽

2020 ◽

pp. 1-16 ◽

Cited By ~ 1

Author(s):

Jessye M. Maxwell ◽

Richard A. Russell ◽

Hei Man Wu ◽

Natasha Sharapova ◽

Peter Banthorpe ◽

...

Keyword(s):

Risk Factors ◽

Adverse Selection ◽

Genetic Variants ◽

Risk Information ◽

Risk Scores ◽

Uk Biobank ◽

Polygenic Risk ◽

Common Genetic Variants ◽

Multifactorial Disorders ◽

The Uk

Abstract During the past decade, genetics research has allowed scientists and clinicians to explore the human genome in detail and reveal many thousands of common genetic variants associated with disease. Genetic risk scores, known as polygenic risk scores (PRSs), aggregate risk information from the most important genetic variants into a single score that describes an individual’s genetic predisposition to a given disease. This article reviews recent developments in the predictive utility of PRSs in relation to a person’s susceptibility to breast cancer and coronary artery disease. Prognostic models for these disorders are built using data from the UK Biobank, controlling for typical clinical and underwriting risk factors. Furthermore, we explore the possibility of adverse selection where genetic information about multifactorial disorders is available for insurance purchasers but not for underwriters. We demonstrate that prediction of multifactorial diseases, using PRSs, provides population risk information additional to that captured by normal underwriting risk factors. This research using the UK Biobank is in the public interest as it contributes to our understanding of predicting risk of disease in the population. Further research is imperative to understand how PRSs could cause adverse selection if consumers use this information to alter their insurance purchasing behaviour.

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