Polygenic risk scores for late smoking initiation associated with the risk of schizophrenia

AbstractPatients with schizophrenia display characteristic smoking-related behaviors and genetic correlations between smoking behaviors and schizophrenia have been identified in European individuals. However, the genetic etiology of the association remains to be clarified. The present study investigated transethnic genetic overlaps between European-based smoking behaviors and the risk of Japanese schizophrenia by conducting polygenic risk score (PRS) analyses. Large-scale European genome-wide association study (GWAS) datasets (n = 24,114–74,035) related to four smoking-related intermediate phenotypes [(i) smoking initiation, (ii) age at smoking initiation, (iii) smoking quantity, and (iv) smoking cessation] were utilized as discovery samples. PRSs derived from these discovery GWASs were calculated for 332 Japanese subjects [schizophrenia patients, their unaffected first-degree relatives (FRs), and healthy controls (HCs)] as a target sample. Based on GWASs of European smoking phenotypes, we investigated the effects of PRSs on smoking phenotypes and the risk of schizophrenia in the Japanese population. Of the four smoking-related behaviors, the PRSs for age at smoking initiation in Europeans significantly predicted the age at smoking initiation (R2 = 0.049, p = 0.026) and the PRSs for smoking cessation significantly predicted the smoking cessation (R2 = 0.092, p = 0.027) in Japanese ever-smokers. Furthermore, the PRSs related to age at smoking initiation in Europeans were higher in Japanese schizophrenia patients than in the HCs and those of the FRs were intermediate between those of patients with schizophrenia and those of the HCs (R2 = 0.015, p = 0.015). In our target subjects, patients with schizophrenia had a higher mean age at smoking initiation (p = 0.018) and rate of daily smoking initiation after age 20 years (p = 0.023) compared with the HCs. A total of 60.6% of the patients started to smoke before the onset of schizophrenia. These findings suggest that genetic factors affecting late smoking initiation are associated with the risk of schizophrenia.

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Polygenic risk scores applied to a single cohort reveal pleiotropy among hundreds of human phenotypes

10.1101/203257 ◽

2017 ◽

Cited By ~ 9

Author(s):

Adam Socrates ◽

Tom Bond ◽

Ville Karhunen ◽

Juha Auvinen ◽

Cornelius A. Rietveld ◽

...

Keyword(s):

Epidemiological Study ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Convincing Evidence ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genetic Associations ◽

Polygenic Risk ◽

Moderate Sample Size ◽

Shared Genetic

AbstractBackgroundThere is now convincing evidence that pleiotropy across the genome contributes to the correlation between human traits and comorbidity of diseases. The recent availability of genome-wide association study (GWAS) results have made the polygenic risk score (PRS) approach a powerful way to perform genetic prediction and identify genetic overlap among phenotypes.Methods and findingsHere we use the PRS method to assess evidence for shared genetic aetiology across hundreds of traits within a single epidemiological study – the Northern Finland Birth Cohort 1966 (NFBC1966). We replicate numerous recent findings, such as a genetic association between Alzheimer’s disease and lipid levels, while the depth of phenotyping in the NFBC1966 highlights a range of novel significant genetic associations between traits.ConclusionsThis study illustrates the power in taking a hypothesis-free approach to the study of shared genetic aetiology between human traits and diseases. It also demonstrates the potential of the PRS method to provide important biological insights using only a single well-phenotyped epidemiological study of moderate sample size (~5k), with important advantages over evaluating genetic correlations from GWAS summary statistics only.

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An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome

10.1101/467910 ◽

2018 ◽

Cited By ~ 1

Author(s):

Tom G. Richardson ◽

Sean Harrison ◽

Gibran Hemani ◽

George Davey Smith

Keyword(s):

Web Application ◽

Large Scale ◽

Complex Disease ◽

Association Studies ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Genetic Liability ◽

Polygenic Risk ◽

The Uk

AbstractThe age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (P<5×l0 05) derived from GWAS and 551 heritable traits from the UK Biobank study (N=334,398). Findings can be investigated using a web application (http://mrcieu.mrsoftware.org/PRS_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility.To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease.

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Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health

European Respiratory Journal ◽

10.1183/13993003.03091-2020 ◽

2020 ◽

pp. 2003091

Author(s):

Satu Strausz ◽

Sanni Ruotsalainen ◽

Hanna M. Ollila ◽

Juha Karjalainen ◽

Tuomo Kiiskinen ◽

...

Keyword(s):

Obstructive Sleep Apnoea ◽

Large Scale ◽

Genome Wide Association Study ◽

Genetic Correlations ◽

Sleep Apnoea ◽

Mendelian Randomisation ◽

Cardiometabolic Health ◽

Inflammatory Rheumatic Diseases ◽

Polygenic Risk Score ◽

Obstructive Sleep

There is currently limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). We aimed at identifying genetic loci associated with OSA risk and to test if OSA and its comorbidities share a common genetic background.We conducted the first large-scale genome-wide association study of OSA using FinnGen Study (217 955 individuals) with 16 761 OSA patients identified using nationwide health registries.We estimated 8.3% [0.06–0.11] heritability and identified five loci associated with OSA (p<5.0×10−8): rs4837016 near GTPase activating protein and VPS9 domains 1 (GAPVD1), rs10928560 near C-X-C motif chemokine receptor 4 (CXCR4), rs185932673 near Calcium/calmodulin-dependent protein kinase ID (CAMK1D) and rs9937053 near Fat mass and obesity-associated protein (FTO) - a variant previously associated with body mass index (BMI). In a BMI-adjusted analysis, an association was observed for rs10507084 near Rhabdomyosarcoma 2 associated transcript (RMST)/NEDD1 gamma-tubulin ring complex targeting factor (NEDD1). We found high genetic correlations between OSA and BMI (rg=0.72 [0.62–0.83]) and with comorbidities including hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), stroke, depression, hypothyroidism, asthma and inflammatory rheumatic diseases (IRD) (rg>0.30). Polygenic risk score (PRS) for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile and Mendelian randomisation supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA and joint genetic basis between OSA and comorbidities.

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Polygenic Risk Scores Augment Stroke Subtyping

Neurology Genetics ◽

10.1212/nxg.0000000000000560 ◽

2021 ◽

Vol 7 (2) ◽

pp. e560

Author(s):

Jiang Li ◽

Durgesh P. Chaudhary ◽

Ayesha Khan ◽

Christoph Griessenauer ◽

David J. Carey ◽

...

Keyword(s):

Ischemic Stroke ◽

Genetic Correlation ◽

Genome Wide Association Study ◽

Low Frequency ◽

European Ancestry ◽

Risk Scores ◽

Polygenic Risk Score ◽

Large Artery ◽

Polygenic Risk ◽

Gene Sets

ObjectiveTo determine whether the polygenic risk score (PRS) derived from MEGASTROKE is associated with ischemic stroke (IS) and its subtypes in an independent tertiary health care system and to identify the PRS derived from gene sets of known biological pathways associated with IS.MethodsControls (n = 19,806/7,484, age ≥69/79 years) and cases (n = 1,184/951 for discovery/replication) of acute IS with European ancestry and clinical risk factors were identified by leveraging the Geisinger Electronic Health Record and chart review confirmation. All Geisinger MyCode patients with age ≥69/79 years and without any stroke-related diagnostic codes were included as low risk control. Genetic heritability and genetic correlation between Geisinger and MEGASTROKE (EUR) were calculated using the summary statistics of the genome-wide association study by linkage disequilibrium score regression. All PRS for any stroke (AS), any ischemic stroke (AIS), large artery stroke (LAS), cardioembolic stroke (CES), and small vessel stroke (SVS) were constructed by PRSice-2.ResultsA moderate heritability (10%–20%) for Geisinger sample as well as the genetic correlation between MEGASTROKE and the Geisinger cohort was identified. Variation of all 5 PRS significantly explained some of the phenotypic variations of Geisinger IS, and the R2 increased by raising the cutoff for the age of controls. PRSLAS, PRSCES, and PRSSVS derived from low-frequency common variants provided the best fit for modeling (R2 = 0.015 for PRSLAS). Gene sets analyses highlighted the association of PRS with Gene Ontology terms (vascular endothelial growth factor, amyloid precursor protein, and atherosclerosis). The PRSLAS, PRSCES, and PRSSVS explained the most variance of the corresponding subtypes of Geisinger IS suggesting shared etiologies and corroborated Geisinger TOAST subtyping.ConclusionsWe provide the first evidence that PRSs derived from MEGASTROKE have value in identifying shared etiologies and determining stroke subtypes.

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Polygenetic Risk Scores for Major Psychiatric Disorders Among Schizophrenia Patients, Their First-Degree Relatives, and Healthy Participants

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyz073 ◽

2020 ◽

Vol 23 (3) ◽

pp. 157-164 ◽

Cited By ~ 2

Author(s):

Kazutaka Ohi ◽

Daisuke Nishizawa ◽

Takamitsu Shimada ◽

Yuzuru Kataoka ◽

Junko Hasegawa ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Psychiatric Disorders ◽

Large Scale ◽

Genome Wide Association Study ◽

Autism Spectrum ◽

Spectrum Disorder ◽

European Ancestry ◽

Risk Scores ◽

Polygenic Risk Score ◽

First Degree Relatives

Abstract Background The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected first-degree relatives and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses. Methods To calculate PRSs for 5 psychiatric disorders (SCZ, bipolar disorder [BIP], major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder) and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target participants [SCZ patients, FRs, and healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders and investigated their effect on risk in Japanese SCZ patients and unaffected first-degree relatives. Results The PRSs obtained from European SCZ and BIP patients were higher in Japanese SCZ patients than in HCs. Furthermore, PRSs differentiating SCZ patients from European BIP patients were higher in Japanese SCZ patients than in HCs. Interestingly, PRSs related to European autism spectrum disorder were lower in Japanese first-degree relatives than in HCs or SCZ patients. The PRSs of autism spectrum disorder were positively correlated with a young onset age of SCZ. Conclusions These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected first-degree relatives may help protect against SCZ development.

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Findings from the Hispanic Community Health Study/Study of Latinos on the Importance of Sociocultural Environmental Interactors: Polygenic Risk Score-by-Immigration and Dietary Interactions

Frontiers in Genetics ◽

10.3389/fgene.2021.720750 ◽

2021 ◽

Vol 12 ◽

Author(s):

Cristin E. McArdle ◽

Hassan Bokhari ◽

Clinton C. Rodell ◽

Victoria Buchanan ◽

Liana K. Preudhomme ◽

...

Keyword(s):

Community Health ◽

Genome Wide Association Study ◽

The United States ◽

European Ancestry ◽

Risk Scores ◽

Health Study ◽

Polygenic Risk Score ◽

Polygenic Risk ◽

Hispanic Community

Introduction: Hispanic/Latinos experience a disproportionate burden of obesity. Acculturation to US obesogenic diet and practices may lead to an exacerbation of innate genetic susceptibility. We examined the role of gene–environment interactions to better characterize the sociocultural environmental determinants and their genome-scale interactions, which may contribute to missing heritability of obesity. We utilized polygenic risk scores (PRSs) for body mass index (BMI) to perform analyses of PRS-by-acculturation and other environmental interactors among self-identified Hispanic/Latino adults from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).Methods: PRSs were derived using genome-wide association study (GWAS) weights from a publicly available, large meta-analysis of European ancestry samples. Generalized linear models were run using a set of a priori acculturation-related and environmental factors measured at visit 1 (2008–2011) and visit 2 (2014–2016) in an analytic subsample of 8,109 unrelated individuals with genotypic, phenotypic, and complete case data at both visits. We evaluated continuous measures of BMI and waist-to-hip ratio. All models were weighted for complex sampling design, combined, and sex-stratified.Results: Overall, we observed a consistent increase of BMI with greater PRS across both visits. We found the best-fitting model adjusted for top five principal components of ancestry, sex, age, study site, Hispanic/Latino background genetic ancestry group, sociocultural factors and PRS interactions with age at immigration, years since first arrival to the United States (p < 0.0104), and healthy diet (p < 0.0036) and explained 16% of the variation in BMI. For every 1-SD increase in PRS, there was a corresponding 1.10 kg/m2 increase in BMI (p < 0.001). When these results were stratified by sex, we observed that this 1-SD effect of PRS on BMI was greater for women than men (1.45 vs. 0.79 kg/m2, p < 0.001).Discussion: We observe that age at immigration and the adoption of certain dietary patterns may play a significant role in modifying the effect of genetic risk on obesity. Careful consideration of sociocultural and immigration-related factors should be evaluated. The role of nongenetic factors, including the social environment, should not be overlooked when describing the performance of PRS or for promoting population health in understudied populations in genomics.

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Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health

10.1101/2020.08.04.235994 ◽

2020 ◽

Author(s):

Satu Strausz ◽

Sanni Ruotsalainen ◽

Hanna M. Ollila ◽

Juha Karjalainen ◽

Mary Reeve ◽

...

Keyword(s):

Obstructive Sleep Apnoea ◽

Large Scale ◽

Genome Wide Association Study ◽

Strong Association ◽

Genetic Correlations ◽

Sleep Apnoea ◽

Cardiometabolic Health ◽

Inflammatory Rheumatic Diseases ◽

Polygenic Risk Score ◽

Obstructive Sleep

AbstractThere is currently only limited understanding of the genetic aetiology of obstructive sleep apnoea (OSA). The aim of our study is to identify genetic loci associated with OSA risk and to test if OSA and its comorbidities share a common genetic background.We conducted the first large-scale genome-wide association study of OSA using FinnGen Study (217,955 individuals) with 16,761 OSA patients identified using nationwide health registries.We estimated 8.3% [0.06-0.11] heritability and identified five loci associated with OSA (P < 5.0 × 10−8): rs4837016 near GTPase activating protein and VPS9 domains 1 (GAPVD1), rs10928560 near C-X-C motif chemokine receptor 4 (CXCR4), rs185932673 near Calcium/calmodulin-dependent protein kinase ID (CAMK1D) and rs9937053 near Fat mass and obesity-associated protein (FTO) - a variant previously associated with body mass index (BMI). In a BMI-adjusted analysis, an association was observed for rs10507084 near Rhabdomyosarcoma 2 associated transcript (RMST)/NEDD1 gamma-tubulin ring complex targeting factor (NEDD1).We found genetic correlations between OSA and BMI (rg=0.72 [0.62-0.83]) and with comorbidities including hypertension, type 2 diabetes (T2D), coronary heart disease (CHD), stroke, depression, hypothyroidism, asthma and inflammatory rheumatic diseases (IRD) (rg > 0.30). Polygenic risk score (PRS) for BMI showed 1.98-fold increased OSA risk between the highest and the lowest quintile and Mendelian randomization supported a causal relationship between BMI and OSA.Our findings support the causal link between obesity and OSA and joint genetic basis between OSA and comorbidities.

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Validation of a Trans-Ancestry Polygenic Risk Score for Type 2 Diabetes in Diverse Populations

10.1101/2021.09.11.21263413 ◽

2021 ◽

Author(s):

Tian Ge ◽

Amit Patki ◽

Vinodh Srinivasasainagendra ◽

Yen-Feng Lin ◽

Marguerite Ryan Irvin ◽

...

Keyword(s):

Risk Factors ◽

Type 2 Diabetes ◽

African American ◽

Large Scale ◽

Association Studies ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk

ABSTRACTType 2 diabetes (T2D) is a worldwide scourge caused by both genetic and environmental risk factors that disproportionately afflicts communities of color. Leveraging existing large-scale genome-wide association studies (GWAS), polygenic risk scores (PRS) have shown promise to complement established clinical risk factors and intervention paradigms, and improve early diagnosis and prevention of T2D. However, to date, T2D PRS have been most widely developed and validated in individuals of European descent. Comprehensive assessment of T2D PRS in non-European populations is critical for an equitable deployment of PRS to clinical practice that benefits global populations. Here we integrate T2D GWAS in European, African American and East Asian populations to construct a trans-ancestry T2D PRS using a newly developed Bayesian polygenic modeling method, and evaluate the PRS in the multi-ethnic eMERGE study, four African American cohorts, and the Taiwan Biobank. The trans-ancestry PRS was significantly associated with T2D status across the ancestral groups examined, and the top 2% of the PRS distribution can identify individuals with an approximately 2.5-4.5 fold of increase in T2D risk, suggesting the potential of using the trans-ancestry PRS as a meaningful index of risk among diverse patients in clinical settings. Our efforts represent the first step towards the implementation of the T2D PRS into routine healthcare.

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An atlas of polygenic risk score associations to highlight putative causal relationships across the human phenome

eLife ◽

10.7554/elife.43657 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 59

Author(s):

Tom G Richardson ◽

Sean Harrison ◽

Gibran Hemani ◽

George Davey Smith

Keyword(s):

Web Application ◽

Large Scale ◽

Complex Disease ◽

Association Studies ◽

Risk Scores ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Genetic Liability ◽

Polygenic Risk ◽

The Uk

The age of large-scale genome-wide association studies (GWAS) has provided us with an unprecedented opportunity to evaluate the genetic liability of complex disease using polygenic risk scores (PRS). In this study, we have analysed 162 PRS (p<5×10−05) derived from GWAS and 551 heritable traits from the UK Biobank study (N = 334,398). Findings can be investigated using a web application (http:‌//‌mrcieu.‌mrsoftware.org/‌PRS‌_atlas/), which we envisage will help uncover both known and novel mechanisms which contribute towards disease susceptibility. To demonstrate this, we have investigated the results from a phenome-wide evaluation of schizophrenia genetic liability. Amongst findings were inverse associations with measures of cognitive function which extensive follow-up analyses using Mendelian randomization (MR) provided evidence of a causal relationship. We have also investigated the effect of multiple risk factors on disease using mediation and multivariable MR frameworks. Our atlas provides a resource for future endeavours seeking to unravel the causal determinants of complex disease.

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O2.4. FUNCTIONAL CONNECTOME-WIDE ASSOCIATIONS OF SCHIZOPHRENIA POLYGENIC RISK

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa028.009 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S4-S5

Author(s):

Hengyi Cao ◽

Hang Zhou ◽

Tyrone Cannon

Keyword(s):

Network Architecture ◽

Large Scale ◽

Genome Wide Association Study ◽

Brain Connectivity ◽

Bipolar Disorders ◽

Principal Component ◽

Risk Scores ◽

Polygenic Risk ◽

Genome Wide ◽

Human Connectome Project

Abstract Background The relationships between schizophrenia polygenic risk and connectome-wide brain connectivity remain unclear. In particular, it is unknown whether and how schizophrenia polygenic risk would influence functional connectivity both at the connectome level and in a state-independent way. In this study, we used multi-paradigm fMRI data from two independent cohorts to investigate these questions. Methods The discovery sample included 623 healthy Caucasian participants (age 28.86 ± 3.63 years, 302 males) acquired from the Human Connectome Project (HCP). All subjects completed fMRI scans for a battery of eight paradigms and had imputed genetic data available. Following the procedures in our prior studies, we constructed whole-brain connectivity matrices for each paradigm in each individual. From these derived matrices, we computed cross-paradigm connectivity (CPC) using principal component analysis. These CPC matrices quantify shared connectivity patterns across all paradigms for each individual and thus represent state-independent “trait” network architecture of each subject. The polygenic risk scores (PRSs) for each subject were calculated based on the genome-wide association study (GWAS) results from the Psychiatric Genomics Consortium. The scores were calculated as the sum of genome-wide risk alleles for each individual, weighted by the corresponding odds ratios to schizophrenia. We report our main findings based on the GWAS-significant threshold (P = 5×10–8). In addition, to test the robustness of our findings, we also calculated PRSs with a set of other thresholds ranging from 5×10–7 to 5×10–2. The network-based statistic (NBS) analysis was performed to associate PRSs with CPC matrices, where age, sex, and head motion were included as covariates. Significance was determined by 10,000 permutations of the original sample. The validation sample included 44 patients with schizophrenia, 43 patients with bipolar disorders, 34 patients with attention deficit hyperactivity disorder, and 77 healthy controls drawn from the Consortium for Neuropsychiatric Phenomics (CNP). All subjects completed a battery of seven fMRI paradigms. We used this sample to examine 1) whether the identified connectomic findings were specifically detected in patients with schizophrenia; and 2) whether these findings could be related to behavioral deficits in patients with schizophrenia. Results In the HCP sample, the NBS analysis revealed a significant association (PFWE < 0.05) between schizophrenia PRS and a large-scale network involving a total of 69 edges connecting between 54 nodes. These nodes were predominantly distributed in the brain’s visual system, default-mode system, and frontoparietal system. Specifically, higher PRSs were associated with lower connectivity for all connections in the identified network (R = -0.37). The results were significant across all paradigms (R < -0.13, P < 0.001) and remained robust across multiple PRS thresholds (R < -0.10, P < 0.02). In the CNP sample, the connectivity of the detected network differed significantly between groups (P = 0.005), which was particularly driven by decreased connectivity in patients with SZ compared with that in HCs (PBonferroni = 0.03). The connectivity of the identified network was significantly correlated with both performance IQ (R = 0.28, P =0.002) and verbal IQ (R = 0.29, P = 0.001). Discussion These findings provide the first evidence for state-independent connectome-wide associations of schizophrenia polygenic risk at the systems level and suggest that disrupted integration of sensori-cognitive information may be a hallmark of genetic effects on the brain that contributes to the pathogenesis of schizophrenia.

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