The impact of sex, age at onset, recurrence, mode of ascertainment and medical complications on the family genetic risk score profiles for alcohol use disorder

2021 ◽  
pp. 1-9
Author(s):  
Kenneth S. Kendler ◽  
Henrik Ohlsson ◽  
Jan Sundquist ◽  
Kristina Sundquist
Keyword(s):  
Alcohol Use ◽  
Genetic Risk ◽  
Criminal Behavior ◽  
Alcohol Use Disorder ◽  
Genetic Risk Score ◽  
Age At Onset ◽  
Risk Scores ◽  
Medical Complications ◽  
The Family ◽  
The Impact

Abstract Background Alcohol use disorder (AUD) is clinically heterogeneous. We examine its potential genetic heterogeneity as a function of sex, age, clinical features and mode of ascertainment. Methods In the Swedish population born 1932–1995 (n = 5 829 952), we examined the genetic risk profiles for AUD, major depression (MD), anxiety disorders, bipolar disorder, drug use disorder (DUD), attention deficit-hyperactivity disorder (ADHD) and criminal behavior (CB) in 361 124 cases of AUD subdivided by sex, age at onset (AAO), recurrence, mode of ascertainment and medical complications. Family genetic risk scores (FGRS), calculated from 1st to 5th-degree relatives controlling of cohabitation, assesses genetic risk from phenotypes in the family, not from DNA variants. Results FGRS profiles differed modestly across sex with all scores higher in females. Differences were more pronounced for AAO and recurrence with the FGRS for AUD, DUD, ADHD and CB substantially higher in cases with early AAO or high recurrence rates. Genetic profiles differed considerably by mode of ascertainment, with higher FGRS for AUD and most other disorders in patients seen in hospital v. primary care settings. Cases of AUD with medical complications had higher FGRS for AUD. AUD cases comorbid with MD and DUD had higher FGRS risk for AUD, but this genetic may be less specific given increases in FGRS for multiple other disorders. Conclusions From a genetic perspective, AUD differs substantially as a function of AAO, recurrence, mode of ascertainment and patterns of comorbidity, suggesting caution in cross-sample comparisons of AUD cohorts that differ in these features.

scholarly journals Interest in Genetic Feedback for Alcohol Use Disorder and Related Substance Use and Psychiatric Outcomes among Young Adults

2020 ◽  
Vol 10 (12) ◽  
pp. 1007
Author(s):  
Morgan Driver ◽  
Sally Kuo ◽  
Danielle Dick ◽  
Keyword(s):  
Substance Use ◽  
Alcohol Use ◽  
Genetic Risk ◽  
Alcohol Use Disorder ◽  
Genetic Risk Score ◽  
Related Substance ◽  
Direct To Consumer ◽  
Sizable Proportion ◽  
Psychiatric Outcomes ◽  
The Individual

An exponential growing number of individuals are accessing genetic risk information via direct to consumer companies. Alcohol dependence is the third most accessed genetic risk score on a publicly available direct to consumer website. Better understanding of the degree to which individuals are interested in receiving personalized genetic feedback, the factors that relate to interest, and genetic knowledge will be critical to lay the foundation for precision medicine initiatives, especially for substance use and psychiatric outcomes, where less is known. To assess interest in receiving genetic feedback for alcohol use disorder (AUD) and understanding of genetic concepts related to psychiatric conditions, we conducted a survey with participants recruited from a registry that enrolled incoming cohorts of freshmen at an urban public university; 205 participants (76.5% female; 58.9% self-reported as White; Mage = 24.48 years) completed the survey. Results indicated that participants are highly interested in receiving genetic feedback for AUD (79.0%) but there is a lack of understanding of complex genetic concepts in a sizable proportion of the sample (25.4%). Additional research is needed to assess how to address this lack of knowledge before genetic feedback for AUD can be returned in a way that benefits the individual.

scholarly journals Maternal half-sibling families with discordant fathers: a contrastive design assessing cross-generational paternal genetic transmission of alcohol use disorder, drug abuse and major depression

2019 ◽  
Vol 50 (6) ◽  
pp. 973-980 ◽  
Author(s):  
Kenneth S. Kendler ◽  
Henrik Ohlsson ◽  
Jan Sundquist ◽  
Kristina Sundquist
Keyword(s):  
Drug Abuse ◽  
Major Depression ◽  
Alcohol Use ◽  
Genetic Risk ◽  
Alcohol Use Disorder ◽  
Educational Achievement ◽  
Prenatal Development ◽  
Genetic Transmission ◽  
The Impact ◽  
Half Sibling

AbstractBackgroundWe introduce and apply an elegant, contrastive genetic-epidemiological design – Maternal Half-Sibling Families with Discordant Fathers – to clarify cross-generational transmission of genetic risk to alcohol use disorder (AUD), drug abuse (DA) and major depression (MD).MethodUsing Swedish national registries, we identified 73 108 eligible pairs of reared together maternal half-siblings and selected those whose biological fathers were discordant for AUD, DA and MD, and had minimal contact with the affected father. We examined differences in outcome in half-siblings with an affected v. unaffected father.ResultsFor AUD, DA and MD, the HR (95% confidence intervals) for the offspring of affected v. unaffected fathers were, respectively, 1.72 (1.61; 1.84), 1.55 (1.41; 1.70) and 1.51 (1.40; 1.64). Paternal DA and AUD, but not MD, predicted risk in offspring for attention deficit hyperactivity disorder, conduct disorder, and poor educational performance and attainment. Offspring of affected v. unaffected fathers had poorer pregnancy outcomes, with the effect strongest for DA and weakest for MD. A range of potential biases and confounders were examined and were not found to alter these findings substantially.ConclusionReared together maternal half-siblings differ in their paternal genetic endowment, sharing the same mother, family, school and community. They can help clarify the nature of paternal genetic effects and produce results consistent with other designs. Paternal genetic risk for DA and AUD have effects on offspring educational achievement, child and adult psychopathology, and possibly prenatal development. The impact of paternal genetic risk for MD is narrower in scope.

Examining interactions between genetic risk for alcohol problems, peer deviance, and interpersonal traumatic events on trajectories of alcohol use disorder symptoms among African American college students

2018 ◽  
Vol 30 (5) ◽  
pp. 1749-1761 ◽  
Author(s):  
Jinni Su ◽  
Sally I-Chun Kuo ◽  
Jacquelyn L. Meyers ◽  
Mignonne C. Guy ◽  
Danielle M. Dick
Keyword(s):  
African American ◽  
Family History ◽  
Alcohol Use ◽  
Genetic Risk ◽  
Alcohol Use Disorder ◽  
Traumatic Events ◽  
Alcohol Problems ◽  
Risk Scores ◽  
Peer Deviance ◽  
History Of

AbstractNumerous studies have demonstrated that genetic and environmental factors interact to influence alcohol problems. Yet prior research has primarily focused on samples of European descent and little is known about gene–environment interactions in relation to alcohol problems in non-European populations. In this study, we examined whether and how genetic risk for alcohol problems and peer deviance and interpersonal traumatic events independently and interactively influence trajectories of alcohol use disorder symptoms in a sample of African American students across the college years (N = 1,119; Mage= 18.44 years). Data were drawn from the Spit for Science study where participants completed multiple online surveys throughout college and provided a saliva sample for genotyping. Multilevel growth curve analyses indicated that alcohol dependence genome-wide polygenic risk scores did not predict trajectory of alcohol use disorder symptoms, while family history of alcohol problems was associated with alcohol use disorder symptoms at the start of college but not with the rate of change in symptoms over time. Peer deviance and interpersonal traumatic events were associated with more alcohol use disorder symptoms across college years. Neither alcohol dependence genome-wide polygenic risk scores nor family history of alcohol problems moderated the effects of these environmental risk factors on alcohol use disorder symptoms. Our findings indicated that peer deviance and experience of interpersonal traumatic events are salient risk factors that elevate risk for alcohol problems among African American college students. Family history of alcohol problems could be a useful indicator of genetic risk for alcohol problems. Gene identification efforts with much larger samples of African descent are needed to better characterize genetic risk for alcohol use disorders, in order to better understand gene–environment interaction processes in this understudied population.

scholarly journals Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis

2013 ◽  
Vol 20 (6) ◽  
pp. 660-668 ◽  
Author(s):  
Hanne F Harbo ◽  
Noriko Isobe ◽  
Pål Berg-Hansen ◽  
Steffan D Bos ◽  
Stacy J Caillier ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Age At Onset ◽  
Human Leukocyte ◽  
Oligoclonal Bands ◽  
Nucleotide Polymorphisms ◽  
Risk Variants ◽  
The Impact ◽  
Genetic Risk Variants

Background: Many genetic risk variants are now well established in multiple sclerosis (MS), but the impact on clinical phenotypes is unclear. Objective: To investigate the impact of established MS genetic risk variants on MS phenotypes, in well-characterized MS cohorts. Methods: Norwegian MS patients ( n = 639) and healthy controls ( n = 530) were successfully genotyped for 61 established MS-associated single nucleotide polymorphisms (SNPs). Data including and excluding Major Histocompatibility Complex (MHC) markers were summed to a MS Genetic Burden (MSGB) score. Study replication was performed in a cohort of white American MS patients ( n = 1997) and controls ( n = 708). Results: The total human leukocyte antigen (HLA) and the non-HLA MSGB scores were significantly higher in MS patients than in controls, in both cohorts ( P << 10−22). MS patients, with and without cerebrospinal fluid (CSF) oligoclonal bands (OCBs), had a higher MSGB score than the controls; the OCB-positive patients had a slightly higher MSGB than the OCB-negative patients. An early age at symptom onset (AAO) also correlated with a higher MSGB score, in both cohorts. Conclusion: The MSGB score was associated with specific clinical MS characteristics, such as OCBs and AAO. This study underlines the need for well-characterized, large cohorts of MS patients, and the usefulness of summarizing multiple genetic risk factors of modest effect size in genotype-phenotype analyses.

scholarly journals Identifying individuals with high risk of Alzheimer’s disease using polygenic risk scores

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ganna Leonenko ◽  
Emily Baker ◽  
Joshua Stevenson-Hoare ◽  
Annerieke Sierksma ◽  
Mark Fiers ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Genetic Risk ◽  
Prediction Accuracy ◽  
Genetic Risk Score ◽  
Low Risk ◽  
Risk Scores ◽  
Sample Mean ◽  
Polygenic Risk ◽  
Reliable Identification

AbstractPolygenic Risk Scores (PRS) for AD offer unique possibilities for reliable identification of individuals at high and low risk of AD. However, there is little agreement in the field as to what approach should be used for genetic risk score calculations, how to model the effect of APOE, what the optimal p-value threshold (pT) for SNP selection is and how to compare scores between studies and methods. We show that the best prediction accuracy is achieved with a model with two predictors (APOE and PRS excluding APOE region) with pT<0.1 for SNP selection. Prediction accuracy in a sample across different PRS approaches is similar, but individuals’ scores and their associated ranking differ. We show that standardising PRS against the population mean, as opposed to the sample mean, makes the individuals’ scores comparable between studies. Our work highlights the best strategies for polygenic profiling when assessing individuals for AD risk.

scholarly journals Mental Health Over Time in a Military Sample: The Impact of Alcohol Use Disorder on Trajectories of Psychopathology After Deployment

2015 ◽  
Vol 28 (6) ◽  
pp. 547-555 ◽  
Author(s):  
Laura Sampson ◽  
Gregory H. Cohen ◽  
Joseph R. Calabrese ◽  
David S. Fink ◽  
Marijo Tamburrino ◽  
...  
Keyword(s):  
Mental Health ◽  
Alcohol Use ◽  
Alcohol Use Disorder ◽  
The Impact ◽  
Over Time

The Impact of Childhood Maltreatment on Age of Onset of Alcohol Use Disorder in Women

2018 ◽  
Vol 24 (6) ◽  
pp. 278-285 ◽  
Author(s):  
Fides Schückher ◽  
Tabita Sellin ◽  
Claudia Fahlke ◽  
Ingemar Engström
Keyword(s):  
Alcohol Use ◽  
Childhood Maltreatment ◽  
Alcohol Use Disorder ◽  
Age Of Onset ◽  
The Impact

scholarly journals Mitigation of Venous Thromboembolism Risk through Favorable Lifestyle: The ARIC Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1151-1151
Author(s):  
Christina Evans ◽  
Ching-Png Hong ◽  
Aaron R Folsom ◽  
Susan Heckbert ◽  
Nicholas Smith ◽  
...  
Keyword(s):  
Venous Thromboembolism ◽  
Genetic Risk ◽  
Genetic Risk Score ◽  
Lifestyle Factors ◽  
Normal Weight ◽  
Common Disease ◽  
High Genetic Risk ◽  
Optimal Health ◽  
Aric Study ◽  
The Impact

Background: Venous thromboembolism (VTE) is a common disease with a strong genetic basis. Unhealthy lifestyle factors contribute to risk, but it is unknown whether healthier lifestyle can mitigate the risk for VTE in those at high genetic risk. We studied whether greater adherence to the American Heart Association's (AHA's) cardiovascular health metric called Life's Simple 7 (LS7) is associated with a lower rate of VTE in individuals with high genetic risk score (GRS) for VTE. Methods: We followed 9,026 middle-aged white participants from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective cohort of 15,792 individuals enrolled in 1987-89. A validated GRS was used, comprising 5 well known genetic conditions associated with VTE (factor V Leiden, prothrombin 20210A, non-O blood group, factor XI rs4241824, and fibrinogen gamma FGG rs2066865). Only white participants were included, as the GRS did not predict VTE in others. AHA's LS7 categories of inadequate, average, and optimal health were determined based on smoking status, body mass index, physical activity, diet, total cholesterol, blood pressure, and fasting glucose. VTE events were adjudicated by expert medical record review. We calculated hazard ratios (HRs) and 95% confidence intervals (CI) of incident VTE by LS7 categories, stratified by GRS (low, intermediate, high), adjusting for age, sex, and education. HRs were also calculated for individual LS7 components stratified by GRS. Results: There were 466 incident VTE over 22.8 years of follow-up. Compared to those with optimal health, those with inadequate LS7 score had higher rates of VTE (5.7% vs. 3.9%). In Figure 1, compared to the high GRS / inadequate LS7 group, the HR of VTE in the low GRS group with optimal health was lowest at 0.39 (95% CI 0.25-0.61), but moreover, the HR in the high GRS group with optimal health was also attenuated to 0.65 (95% CI 0.48-0.89). The pattern of association was similar for provoked and unprovoked VTE. Of the LS7 components, obesity was most strongly related to VTE. In Figure 2, compared to obese / high GRS participants, the HR of VTE with normal weight / low GRS was 0.36 (95% CI 0.23-0.57), while the HR in high GRS / normal weight participants was reduced by 45%, at 0.55 (95% CI 0.4-0.76). Conclusion: Among all participants, even those at high genetic risk, healthier lifestyle factors, particularly obesity, were associated with decreased incidence of VTE. Further studies should determine the impact of lifestyle change among patients at high genetic risk of VTE, such as in thrombophilic families. Disclosures Heckbert: National Institutes of Health: Other: Grants.

scholarly journals Sex Modifies the Effect of Genetic Risk Scores for Polycystic Ovary Syndrome on Metabolic Phenotypes

2021 ◽  
Author(s):  
Ky'Era V. Actkins ◽  
Genevieve Jean-Pierre ◽  
Melinda C. Aldrich ◽  
Digna R. Velez Edwards ◽  
Lea K. Davis
Keyword(s):  
Polycystic Ovary Syndrome ◽  
Genetic Risk ◽  
Polycystic Ovary ◽  
Medical Center ◽  
Genetic Risk Score ◽  
Risk Scores ◽  
Ovary Syndrome ◽  
Biological Variables ◽  
Increased Risk ◽  
The Relationship

Females with polycystic ovary syndrome (PCOS), the most common endocrine disorder in women, have an increased risk of developing metabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). Furthermore, while only diagnosable in females, males with a family history of PCOS can also exhibit a poor cardiometabolic profile. Therefore, we aimed to elucidate the role of sex in the relationship between PCOS and its comorbidities by conducting bidirectional genetic risk score analyses in both sexes. We conducted a phenome-wide association study (PheWAS) using PCOS polygenic risk scores (PCOSPRS) to understand the pleiotropic effects of PCOS genetic liability across 1,380 medical conditions in females and males recorded in the Vanderbilt University Medical Center electronic health record (EHR) database. After adjusting for age and genetic ancestry, we found that European descent males with higher PCOSPRS were significantly more likely to develop cardiovascular diseases than females at the same level of genetic risk, while females had a higher odds of developing T2D. Based on observed significant associations, we tested the relationship between PRS for comorbid conditions (e.g., T2D, body mass index, hypertension, etc.) and found that only PRS generated for BMI and T2D were associated with a PCOS diagnosis. We then further decomposed the T2DPRS association with PCOS by adjusting the model for measured BMI and BMIresidual (enriched for the environmental contribution to BMI). Results demonstrated that genetically regulated BMI primarily accounted for the relationship between T2DPRS and PCOS. This was further supported in a mediation analysis, which only revealed clinical BMI measurements, but not BMIresidual, as a strong mediator for both sexes. Overall, our findings show that the genetic architecture of PCOS has distinct metabolic sex differences, but these associations are only apparent when PCOSPRS is explicitly modeled. It is possible that these pathways are less explained by the direct genetic risk of metabolic traits than they are by the risk factors shared between them, which can be influenced by biological variables such as sex.

scholarly journals Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors: results from the prospective TEDDY study

2018 ◽  
Vol 56 (9) ◽  
pp. 602-605 ◽  
Author(s):  
Andreas Beyerlein ◽  
Ezio Bonifacio ◽  
Kendra Vehik ◽  
Markus Hippich ◽  
Christiane Winkler ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Risk Score ◽  
Genetic Risk ◽  
Genetic Factors ◽  
Genetic Risk Score ◽  
Risk Scores ◽  
Islet Autoimmunity ◽  
Islet Autoantibody ◽  
Clinical Type

BackgroundProgression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown.MethodsIn 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression.ResultsIslet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93).ConclusionsGenetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.

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