scholarly journals Genetically Determined Smoking Behavior and Risk of Nontraumatic Subarachnoid Hemorrhage

Stroke ◽  
2021 ◽  
Vol 52 (2) ◽  
pp. 582-587
Author(s):  
Julián N. Acosta ◽  
Natalia Szejko ◽  
Cameron P. Both ◽  
Kevin Vanent ◽  
Rommell B. Noche ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Genetic Susceptibility ◽  
Risk Score ◽  
Smoking Behavior ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Inverse Variance ◽  
Increased Risk ◽  
Susceptibility To Smoking ◽  
Weighted Median

Background and Purpose: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to nontraumatic subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and the risk of SAH has not been established. Using Mendelian randomization (MR) analyses, we tested the hypothesis that smoking is causally linked to the risk of SAH. Methods: We conducted a 1-sample MR study using data from the UK Biobank, a large cohort study that enrolled over 500 000 Britons aged 40 to 69 from 2006 to 2010. Participants of European descent were included. SAH cases were ascertained using a combination of self-reported, electronic medical record, and death registry data. As the instrument, we built a polygenic risk score using independent genetic variants known to associate ( P <5 ×10 − 8 ) with smoking behavior. This polygenic risk score represents the genetic susceptibility to smoking initiation. The primary MR analysis utilized the ratio method. Secondary MR analyses included the inverse variance weighted and weighted median methods. Results: A total of 408 609 study participants were evaluated (mean age, 57 [SD 8], female sex, 220 937 [54%]). Among these, 132 566 (32%) ever smoked regularly, and 904 (0.22%) had a SAH. Each additional SD of the smoking polygenic risk score was associated with 21% increased risk of smoking (odds ratio [OR], 1.21 [95% CI, 1.20–1.21]; P <0.001) and a 10% increased risk of SAH (OR, 1.10 [95% CI, 1.03–1.17]; P =0.006). In the primary MR analysis, genetic susceptibility to smoking was associated with a 63% increase in the risk of SAH (OR, 1.63 [95% CI, 1.15–2.31]; P =0.006). Secondary analyses using the inverse variance weighted method (OR, 1.57 [95% CI, 1.13–2.17]; P =0.007) and the weighted median method (OR, 1.74 [95% CI, 1.06–2.86]; P =0.03) yielded similar results. There was no significant pleiotropy (MR-Egger intercept P =0.39; MR Pleiotropy Residual Sum and Outlier global test P =0.69). Conclusions: These findings provide evidence for a causal link between smoking and the risk of SAH.

scholarly journals Polygenic risk for schizophrenia, transition and cortical gyrification: a high-risk study

2017 ◽  
Vol 48 (9) ◽  
pp. 1532-1539 ◽  
Author(s):  
E. Neilson ◽  
C. Bois ◽  
T.-K. Clarke ◽  
L. Hall ◽  
E. C. Johnstone ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Familial Risk ◽  
Positive Association ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Score Analysis ◽  
Increased Risk ◽  
Heritable Disorder ◽  
Diagnostic Symptoms

AbstractBackgroundSchizophrenia is a highly heritable disorder, linked to several structural abnormalities of the brain. More specifically, previous findings have suggested that increased gyrification in frontal and temporal regions are implicated in the pathogenesis of schizophrenia.MethodsThe current study included participants at high familial risk of schizophrenia who remained well (n= 31), who developed sub-diagnostic symptoms (n= 28) and who developed schizophrenia (n= 9) as well as healthy controls (HC) (n= 16). We first tested whether individuals at high familial risk of schizophrenia carried an increased burden of trait-associated alleles using polygenic risk score analysis. We then assessed the extent to which polygenic risk was associated with gyral folding in the frontal and temporal lobes.ResultsWe found that individuals at high familial risk of schizophrenia who developed schizophrenia carried a significantly greater burden of risk-conferring variants for the disorder compared to those at high risk (HR) who developed sub-diagnostic symptoms or remained well and HC. Furthermore, within the HR cohort, there was a significant and positive association between schizophrenia polygenic risk score and bilateral frontal gyrification.ConclusionsThese results suggest that polygenic risk for schizophrenia impacts upon early neurodevelopment to confer greater gyral folding in adulthood and an increased risk of developing the disorder.

Abstract 66: Causal Associations Between Genetically-determined Smoking and Risk of Subarachnoid Hemorrhage

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Julian N Acosta ◽  
Cameron Both ◽  
Stacy Brown ◽  
Audrey Leasure ◽  
Kevin N Vanent ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Smoking Behavior ◽  
Population Based ◽  
European Ancestry ◽  
Ratio Method ◽  
Polygenic Risk Score ◽  
Primary Analysis ◽  
Increased Risk ◽  
Secondary Analyses ◽  
Genetically Determined

Introduction: Animal and observational studies indicate that smoking is a risk factor for aneurysm formation and rupture, leading to subarachnoid hemorrhage (SAH). However, a definitive causal relationship between smoking and SAH has not been established. We leveraged the causal properties of mutation-disease associations to test the hypothesis that smoking is causally linked to SAH. Methods: We conducted a one-sample Mendelian Randomization (MR) study within the UK Biobank, a prospective, population-based observational study. We restricted the analysis to study participants with genetically-confirmed European ancestry. SAH cases were ascertained using previously validated codes. As the instrument, we built a polygenic risk score (PRS) using independent (R2<0.1) genetic variants known to be associated (p<5x10-8) with smoking. For the primary MR analysis, we implemented the ratio method using the estimates obtained from testing the PRS for association with risk of SAH and smoking. In secondary analyses, we implemented the inverse-variance weighted (IVW) and weighted median (WM) methods. Pleiotropy was assessed via the MR-Egger approach. Results: We included a total of 408,622 individuals in this study (mean age 57 [SD 8], female sex 220,944 [54%]). Of these, 132,568 (32%) ever smoked regularly and 904 (0.22%) had an SAH. Each additional standard deviation of the smoking PRS was associated with a 9% increased risk of SAH (OR 1.09, 95%CI 1.03-1.17; p=0.006) and 21% increased risk of smoking (OR 1.21, 95%CI 1.2-1.21; p=1x10-16). In the primary analysis, genetically-determined smoking was associated with a 63% increase in risk of SAH (OR 1.63, 95%CI 1.15-2.30; p=0.006). Secondary analyses using the IVW method (OR 1.57, 95%CI 1.13-2.17; p=0.007) and the WM method (OR 1.74, 95%CI 1.06-2.86; p=0.028) yielded comparable results. There was no significant pleiotropy (MR-Egger intercept p=0.38). Conclusion: Genetically-determined smoking is strongly associated with the risk of SAH. These findings provide evidence for a causal link between smoking and the occurrence of this often-debilitating condition. Interventions aimed at reducing smoking behavior could offer significant benefits, especially to those at high risk of SAH.

scholarly journals Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia

2020 ◽  
Author(s):  
Antoine Rimbert ◽  
Xavier Vanhoye ◽  
Dramane Coulibaly ◽  
Marie Marrec ◽  
Matthieu Pichelin ◽  
...  
Keyword(s):  
Liver Injury ◽  
Risk Score ◽  
Clinical Care ◽  
Liver Steatosis ◽  
Genetic Diagnosis ◽  
Density Lipoprotein ◽  
Polygenic Risk Score ◽  
Nonalcoholic Fatty Liver ◽  
Polygenic Risk ◽  
Increased Risk

Objective: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the APOB and PCSK9 genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, P <0.001) and liver injury (47% versus 0%) compared with polygenic hypobetalipoproteinemia. Conclusions: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients.

P.0580 A polygenic risk score predicts an increased risk of depression in mentally healthy young adults

2021 ◽  
Vol 53 ◽  
pp. S425-S426
Author(s):  
A. Kazantseva ◽  
Y. Davydova ◽  
R. Enikeeva ◽  
R. Mustafin ◽  
M. Lobaskova ◽  
...  
Keyword(s):  
Young Adults ◽  
Risk Score ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Increased Risk

scholarly journals Prostate cancer risk prediction using a polygenic risk score

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Csilla Sipeky ◽  
Kirsi M. Talala ◽  
Teuvo L. J. Tammela ◽  
Kimmo Taari ◽  
Anssi Auvinen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Risk Score ◽  
Prostate Cancer Risk ◽  
Population Based ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Randomised Study ◽  
Additional Information ◽  
Increased Risk ◽  
Hereditary Factors

Abstract Hereditary factors have a strong influence on prostate cancer (PC) risk and poorer outcomes, thus stratification by genetic factors addresses a critical need for targeted PC screening and risk-adapted follow-up. In this Finnish population-based retrospective study 2283 clinically diagnosed and 455 screen-detected patients from the Finnish Randomised Study of Screening for Prostate Cancer (FinRSPC), 2400 healthy individuals have been involved. Individual genetic risk through establishment of a polygenic risk score based on 55 PC risk SNPs identified through the Finnish subset of the Collaborative Oncological Gene-Environment Study was assessed. Men with PC had significantly higher median polygenic risk score compared to the controls (6.59 vs. 3.83, P < 0.0001). The polygenic risk score above the control median was a significant predictor of PC (OR 2.13, 95% CI 1.90–2.39). The polygenic risk score predicted the risk of PC with an AUC of 0.618 (95% CI 0.60–0.63). Men in the highest polygenic risk score quartile were 2.8—fold (95% CI 2.4–3.30) more likely to develop PC compared with men in the lowest quartile. In the FinRSPC cohort, a significantly higher percentage of men had a PSA level of ≥ 4 ng/mL in polygenic risk score quartile four compared to quartile one (18.7% vs 8.3%, P < 0.00001). Adding the PRS to a PSA-only model contributed additional information in predicting PC in the FinRSPC model. Results strongly suggest that use of the polygenic risk score would facilitate the identification of men at increased risk for PC.

scholarly journals Polygenic Risk Score Prediction for Endometriosis

2021 ◽  
Vol 3 ◽  
Author(s):  
Kirstine Kloeve-Mogensen ◽  
Palle Duun Rohde ◽  
Simone Twisttmann ◽  
Marianne Nygaard ◽  
Kristina Magaard Koldby ◽  
...  
Keyword(s):  
Risk Score ◽  
Genome Wide Association Study ◽  
Polygenic Risk Score ◽  
Uk Biobank ◽  
Standard Deviation Increase ◽  
Polygenic Risk ◽  
Clinical Risk ◽  
Risk Variants ◽  
Increased Risk ◽  
The Uk

Endometriosis is a major health care challenge because many young women with endometriosis go undetected for an extended period, which may lead to pain sensitization. Clinical tools to better identify candidates for laparoscopy-guided diagnosis are urgently needed. Since endometriosis has a strong genetic component, there is a growing interest in using genetics as part of the clinical risk assessment. The aim of this work was to investigate the discriminative ability of a polygenic risk score (PRS) for endometriosis using three different cohorts: surgically confirmed cases from the Western Danish endometriosis referral Center (249 cases, 348 controls), cases identified from the Danish Twin Registry (DTR) based on ICD-10 codes from the National Patient Registry (140 cases, 316 controls), and replication analysis in the UK Biobank (2,967 cases, 256,222 controls). Patients with adenomyosis from the DTR (25 cases) and from the UK Biobank (1,883 cases) were included for comparison. The PRS was derived from 14 genetic variants identified in a published genome-wide association study with more than 17,000 cases. The PRS was associated with endometriosis in surgically confirmed cases [odds ratio (OR) = 1.59, p = 2.57× 10−7] and in cases from the DTR biobank (OR = 1.50, p = 0.0001). Combining the two Danish cohorts, each standard deviation increase in PRS was associated with endometriosis (OR = 1.57, p = 2.5× 10−11), as well as the major subtypes of endometriosis; ovarian (OR = 1.72, p = 6.7× 10−5), infiltrating (OR = 1.66, p = 2.7× 10−9), and peritoneal (OR = 1.51, p = 2.6 × 10−3). These findings were replicated in the UK Biobank with a much larger sample size (OR = 1.28, p &lt; 2.2× 10−16). The PRS was not associated with adenomyosis, suggesting that adenomyosis is not driven by the same genetic risk variants as endometriosis. Our results suggest that a PRS captures an increased risk of all types of endometriosis rather than an increased risk for endometriosis in specific locations. Although the discriminative accuracy is not yet sufficient as a stand-alone clinical utility, our data demonstrate that genetics risk variants in form of a simple PRS may add significant new discriminatory value. We suggest that an endometriosis PRS in combination with classical clinical risk factors and symptoms could be an important step in developing an urgently needed endometriosis risk stratification tool.

scholarly journals Effect of APOE and a polygenic risk score on incident dementia and cognitive decline in a healthy older population

2020 ◽  
Author(s):  
Moeen Riaz ◽  
Aamira Huq ◽  
Joanne Ryan ◽  
Suzanne G Orchard ◽  
Jane Tiller ◽  
...  
Keyword(s):  
Relative Risk ◽  
Cognitive Decline ◽  
Risk Score ◽  
Cumulative Incidence ◽  
Genetic Factors ◽  
Polygenic Risk Score ◽  
Older Individuals ◽  
Polygenic Risk ◽  
Increased Risk ◽  
Incidence Of Dementia

AbstractImportanceFew studies have measured the effect of genetic factors on dementia and cognitive decline in a population of healthy older individuals followed prospectively.ObjectiveTo examine the effect of Apolipoprotein E (APOE) genotypes and a polygenic risk score (PRS) on incident dementia and cognitive decline in a longitudinal cohort of healthy older people.Design, Setting and ParticipantsPost-hoc genetic analysis of a randomized clinical trial population - the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrollment, participants had no history of diagnosed dementia, atherothrombotic cardiovascular disease, or permanent physical disability and were without cognitive impairment.Main Outcomes and MeasuresDementia (adjudicated trial endpoint) and cognitive decline, defined as a >1.5 standard deviation decline in test score for either global cognition, episodic memory, language/executive function or psychomotor speed, versus baseline scores. Cumulative incidence curves for all-cause dementia and cognitive decline were calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non-APOE variants.Results12,978 participants with European ancestry were included; 54.8% were female, and average age at baseline was 75 years (range 70 to 96). During a median 4.5 years of follow-up, 324 (2.5%) participants developed dementia and 503 (3.8%) died. Cumulative incidence of dementia to age 85 years was estimated to be 7.4% in all participants, 12.6% in APOE ε4 heterozygotes, 26.6% in ε4 homozygotes, 9.6% in the high PRS tertile, and 7.3% in the low PRS tertile. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3-fold increased risk of dementia and a 1.4/1.8-fold increased risk of cognitive decline, versus ε3/ε3 (P<0.001 for both). A high PRS (top tertile) was associated with a 1.4-fold increase risk of dementia, versus the low tertile (CI 1.04-1.76, P=0.02), but was not associated with cognitive decline risk (CI 0.96-1.22, P = 0.18).Conclusions and RelevanceIncidence of dementia among healthy older individuals is low across all genotypes; however, APOE ε4 and high PRS increase relative risk. APOE ε4 is associated with cognitive decline, but PRS is not.KEY POINTSQuestionHow do genetic factors influence the risk of dementia and cognitive decline among healthy older individuals?FindingsWe studied cumulative incidence of dementia and cognitive decline in 12,978 healthy older individuals without cardiovascular disease or cognitive impairment at enrollment, stratified by APOE genotype and a polygenic risk score (PRS). APOE ε4 and PRS increased the relative risk of dementia, but cumulative incidence was low across all genotypes. APOE genotypes were associated with cognitive decline, but PRS was not.MeaningIncidence of dementia is low among healthy older individuals; however, genetic factors still increase relative risk.

scholarly journals Sex-Stratified Polygenic Risk Score Identifies Individuals at Increased Risk of Basal Cell Carcinoma

2020 ◽  
Vol 140 (5) ◽  
pp. 971-975
Author(s):  
Michelle R. Roberts ◽  
Joanne E. Sordillo ◽  
Peter Kraft ◽  
Maryam M. Asgari
Keyword(s):  
Basal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Risk Score ◽  
Basal Cell ◽  
Polygenic Risk Score ◽  
Polygenic Risk ◽  
Increased Risk

scholarly journals Brugada Syndrome: Oligogenic or Mendelian Disease?

2020 ◽  
Vol 21 (5) ◽  
pp. 1687 ◽  
Author(s):  
Michelle M. Monasky ◽  
Emanuele Micaglio ◽  
Giuseppe Ciconte ◽  
Carlo Pappone
Keyword(s):  
General Population ◽  
Risk Score ◽  
Brugada Syndrome ◽  
Heart Function ◽  
Polygenic Risk Score ◽  
Mendelian Disease ◽  
Single Mutation ◽  
Polygenic Risk ◽  
Increased Risk ◽  
Family Segregation

Brugada syndrome (BrS) is diagnosed by a coved-type ST-segment elevation in the right precordial leads on the electrocardiogram (ECG), and it is associated with an increased risk of sudden cardiac death (SCD) compared to the general population. Although BrS is considered a genetic disease, its molecular mechanism remains elusive in about 70–85% of clinically-confirmed cases. Variants occurring in at least 26 different genes have been previously considered causative, although the causative effect of all but the SCN5A gene has been recently challenged, due to the lack of systematic, evidence-based evaluations, such as a variant’s frequency among the general population, family segregation analyses, and functional studies. Also, variants within a particular gene can be associated with an array of different phenotypes, even within the same family, preventing a clear genotype–phenotype correlation. Moreover, an emerging concept is that a single mutation may not be enough to cause the BrS phenotype, due to the increasing number of common variants now thought to be clinically relevant. Thus, not only the complete list of genes causative of the BrS phenotype remains to be determined, but also the interplay between rare and common multiple variants. This is particularly true for some common polymorphisms whose roles have been recently re-evaluated by outstanding works, including considering for the first time ever a polygenic risk score derived from the heterozygous state for both common and rare variants. The more common a certain variant is, the less impact this variant might have on heart function. We are aware that further studies are warranted to validate a polygenic risk score, because there is no mutated gene that connects all, or even a majority, of BrS cases. For the same reason, it is currently impossible to create animal and cell line genetic models that represent all BrS cases, which would enable the expansion of studies of this syndrome. Thus, the best model at this point is the human patient population. Further studies should first aim to uncover genetic variants within individuals, as well as to collect family segregation data to identify potential genetic causes of BrS.

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