Fast and accurate Bayesian polygenic risk modeling with variational inference

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Relationships between substance abuse/dependence and psychiatric disorders based on polygenic scores

Genetic susceptibility to substance use disorders (SUDs) is partially shared between substances. Heritability of any substance dependence, estimated as 54%, is partly explained by additive effects of common variants. Comorbidity between SUDs and other psychiatric disorders is frequent. The present study aims to analyze the additive role of common variants in this comorbidity using polygenic scores (PGSs) based on genome‐wide association study discovery samples of schizophrenia (SCZ), bipolar disorder, attention‐deficit/hyperactivity disorder, autism spectrum disorder, major depressive disorder and anxiety disorders, available from large consortia. PGSs were calculated for 534 patients meeting DSM‐IV criteria for dependence of a substance and abuse/dependence of another substance between alcohol, tobacco, cannabis, cocaine, opiates, hypnotics, stimulants, hallucinogens and solvents; and 587 blood donors from the same population, Iberians from Galicia, as controls. Significance of the PGS and percentage of variance explained were calculated by logistic regression. Using discovery samples of similar size, significant associations with SUDs were detected for SCZ PGS. SCZ PGS explained more variance in SUDs than in most psychiatric disorders. Cross‐disorder PGS based on five psychiatric disorders was significant after adjustment for the effect of SCZ PGS. SCZ PGS was significantly higher in women than in men abusing alcohol. Our findings indicate that SUDs share genetic susceptibility with SCZ to a greater extent than with other psychiatric disorders, including externalizing disorders such as attention‐deficit/hyperactivity disorder. Women have lower probability to develop substance abuse/dependence than men at similar PGS probably because of a higher social pressure against excessive drug use in women.     

Educational attainment polygenic score predicts inhibitory control and academic skills in early and middle childhood

Inhibitory control skills are important for academic outcomes across childhood, but it is unknown whether inhibitory control is implicated in the association between genetic variation and academic performance. This study examined the relationship between a GWAS-based (EduYears) polygenic score indexing educational attainment (EA PGS) and inhibitory control in early (M_age = 3.80 years) and middle childhood (M_age = 9.18 years), and whether inhibitory control in early childhood mediated the relation between EA PGS and academic skills. The sample comprised 731 low-income and racially/ethnically diverse children and their families from the longitudinal early steps multisite study. EA PGS predicted middle childhood inhibitory control (estimate = 0.09, SE = 0.05, p < 0.05) and academic skills (estimate = 0.18, SE = 0.05, p < 0.01) but did not predict early childhood inhibitory control (estimate = 0.08, SE = 0.05, p = 0.11); thus, mediation was not tested. Sensitivity analyses showed that effect sizes were similar across European and African American groups. This study suggests that inhibitory control could serve as a potential mechanism linking genetic differences to educational outcomes.     

Dissecting the polygenic basis of atherosclerosis via disease-associated cell state signatures

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Referent sampling,family history and relative risk: the role of length-biased sampling

Familial risk of disease is often assessed using case control studies based on referent databases. A referent database is a collection of family histories of cases typically assembled as a result of one family member being diagnosed with disease. This sampling scheme is equivalent to sampling families proportional to their size. The larger the family, the greater the probability of finding the family in the referent registry. This phenomena is known as length-biased sampling. The consequence of this kind of sampling is to bias the regression estimate associated with family history. The estimate is typically inflated in comparison to what is true for the actual population.     

Association between polygenic liability for schizophrenia and substance involvement: A nationwide population‐based study in Taiwan

Schizophrenia and substance involvement frequently co‐occur in individuals, and a bidirectional relationship between the two has been proposed; shared underlying genetic factors could be an alternative explanation. This study investigated the genetic overlap between schizophrenia and substance involvement, including tobacco, alcohol and betel nut use. The study subjects were recruited from the Taiwan Biobank, and genome‐wide genotyping data was available for 18 327 participants without schizophrenia. We calculated the Psychiatric Genomics Consortium‐derived polygenic risk score (PRS) for schizophrenia in each participant. The significance of the schizophrenia PRS associated with substance involvement was evaluated using a regression model with adjustments for gender, age and population stratification components. The modified effect of gender or birth decade was also explored. The schizophrenia PRS was positively associated with lifetime tobacco smoking in women (OR in per SD increase in PRS = 1.12 with 95% CI 1.04‐1.20, P = .002), but not in men (OR = 0.99 with 95% CI 0.95‐1.04, P = .74), and the gender‐PRS interaction reached significance (P = .006). The OR between PRS and lifetime tobacco smoking increased with the birth decade (P of birth decade‐PRS interaction = .0002). In women, OR increased from 0.97 (P = .85) for subjects with a birth decade before 1950 to 1.21 (P = .04) for subjects with a birth decade after 1980; in men, the corresponding OR increased from 0.88 (P = .04) to 1.13 (P = .11). There was no association between schizophrenia PRS and alcohol/betel nut use phenotypes. This study provides evidence for the genetic overlap between schizophrenia and tobacco use in women, and this overlap was stronger in the younger population.     

Leveraging related health phenotypes for polygenic prediction of impulsive choice,impulsive action,and impulsive personality traits in 1534 European ancestry community adults

Impulsivity refers to a number of conceptually related phenotypes reflecting self-regulatory capacity that are considered promising endophenotypes for mental and physical health. Measures of impulsivity can be broadly grouped into three domains, namely, impulsive choice, impulsive action, and impulsive personality traits. In a community-based sample of ancestral Europeans (n = 1534), we conducted genome-wide association studies (GWASs) of impulsive choice (delay discounting), impulsive action (behavioral inhibition), and impulsive personality traits (UPPS-P), and evaluated 11 polygenic risk scores (PRSs) of phenotypes previously linked to self-regulation. Although there were no individual genome-wide significant hits, the neuroticism PRS was positively associated with negative urgency (adjusted R² = 1.61%, p = 3.6 × 10⁻⁷) and the educational attainment PRS was inversely associated with delay discounting (adjusted R² = 1.68%, p = 2.2 × 10⁻⁷). There was also evidence implicating PRSs of attention-deficit/hyperactivity disorder, externalizing, risk-taking, smoking cessation, smoking initiation, and body mass index with one or more impulsivity phenotypes (adjusted R²s: 0.35%–1.07%; FDR adjusted ps = 0.05–0.0006). These significant associations between PRSs and impulsivity phenotypes are consistent with established genetic correlations. The combined PRS explained 0.91%–2.46% of the phenotypic variance for individual impulsivity measures, corresponding to 8.7%–32.5% of their reported single-nucleotide polymorphism (SNP)-based heritability, suggesting a non-negligible portion of the SNP-based heritability can be recovered by PRSs. These results support the predictive validity and utility of PRSs, even derived from related phenotypes, to inform the genetics of impulsivity phenotypes.     

Subspecies boundaries and recent evolution history of the common pheasant (Phasianus colchicus) across China

The mitochondrial DNA (mtDNA) control region of two hundreds and thirty-six common pheasants (belonging to fourteen subspecies collected at twenty-eight localities) was used to investigate the subspecies status of Phasianus colchicus. Eighty-nine variable sites defined one hundred and thirty-nine haplotypes. Phylogenetic analysis of haplotypes revealed that P. c. shawii, P. c. mongolicus and P. c. suehschanensis were monophyletic. P. c. shawii and P. c. mongolicus were isolated by the Taklimakan, the Bardain, the Jaran and the Gurbantonggut Deserts where the two subspecies evolved independently. P. c. suehschanensis was isolated by the forest and mountains in the Sichuan Basin where it evolved independently. Further eleven subspecies were identified and split into the western and eastern groups. The divergence occurred in the late Pleistocene when the arid, semi-arid and monsoon regions formed, and it was induced by the isolation from the Qinling and Taihang Mountains. Fst-values decreased from 0.543 (for twenty-eight populations) to 0.541 (for fourteen subspecies). In light of these results, we suggest that the currently recognized subspecies do not reflect the evolutionary history of the common pheasant.     

Genetic trade‐offs between complex diseases and longevity

Longevity was influenced by many complex diseases and traits. However, the relationships between human longevity and genetic risks of complex diseases were not broadly studied. Here, we constructed polygenic risk scores (PRSs) for 225 complex diseases/traits and evaluated their relationships with human longevity in a cohort with 2178 centenarians and 2299 middle‐aged individuals. Lower genetic risks of stroke and hypotension were observed in centenarians, while higher genetic risks of schizophrenia (SCZ) and type 2 diabetes (T2D) were detected in long‐lived individuals. We further stratified PRSs into cell‐type groups and significance‐level groups. The results showed that the immune component of SCZ genetic risk was positively linked to longevity, and the renal component of T2D genetic risk was the most deleterious. Additionally, SNPs with very small p‐values (p ≤ 1x10^‐5) for SCZ and T2D were negatively correlated with longevity. While for the less significant SNPs (1x10^‐5 < p ≤ 0.05), their effects on disease and longevity were positively correlated. Overall, we identified genetically informed positive and negative factors for human longevity, gained more insights on the accumulation of disease risk alleles during evolution, and provided evidence for the theory of genetic trade‐offs between complex diseases and longevity.     

Association between family cancer history and risk of pancreatic cancer

PurposeFamily history of pancreatic adenocarcinoma is an established risk factor for the disease. However, associations of pancreatic cancer with other familial cancers are less clear. We analyzed data from the Queensland Pancreatic Cancer Study (QPCS), an Australian population-based case-control study, to investigate associations between family history of various cancer types and risk of pancreatic cancer.Materials and methodsOur study included 591 pancreatic cancer patients and 646 controls, all of whom self-reported the histories of cancer in their first-degree relatives. We used logistic regression to estimate adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Based on our results, we conducted a systematic literature review using the Medline (OVID) database to identify articles pertaining to the association between family history of melanoma and risk of pancreatic cancer. A meta-analysis including associations in five published studies, unpublished results from a study co-author and the QPCS results was then performed using the DerSimonian and Laird random-effects model.ResultsCases were more likely than controls to report a family history of pancreatic cancer (OR 2.20, 95% CI 1.16–4.19) and melanoma (OR 1.74, 95% CI 1.03–2.95), but not of breast, ovarian, respiratory, other gastrointestinal or prostate cancer. Meta-analysis of melanoma family history and pancreatic cancer risk yielded an OR of 1.22 (95% CI 1.00–1.51).ConclusionsOur results yield further evidence of increased risk of pancreatic cancer in those with family histories of the disease. We also provide suggestive evidence of an association between family history of melanoma and risk of pancreatic cancer.     

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

Few studies have measured the effect of genetic factors on dementia and cognitive decline in healthy older individuals followed prospectively. We studied cumulative incidence of dementia and cognitive decline, stratified by APOE genotypes and polygenic risk score (PRS) tertiles, in 12,978 participants of the ASPirin in Reducing Events in the Elderly (ASPREE) trial. At enrolment, participants had no history of diagnosed dementia, cardiovascular disease, physical disability or cognitive impairment. Dementia (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 for all‐cause dementia and cognitive decline was calculated with mortality as a competing event, stratified by APOE genotypes and tertiles of a PRS based on 23 common non‐APOE variants. During a median 4.5 years of follow‐up, 324 participants developed dementia, 503 died. Cumulative incidence of dementia to age 85 years was 7.4% in all participants, 12.6% in APOE ε3/ε4 and 26.6% in ε4/ε4. APOE ε4 heterozygosity/homozygosity was associated with a 2.5/6.3‐fold increased dementia risk and 1.4/1.8‐fold cognitive decline risk, versus ε3/ε3 (p < 0.001 for both). High PRS tertile was associated with a 1.4‐fold dementia risk versus low (CI 1.04–1.76, p = 0.02), but was not associated with cognitive decline (CI 0.96–1.22, p = 0.18). Incidence 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.     

Population based family history analysis of Brahmins in a small town in India for the prevalence of type-2 diabetes mellitus

OBJECTIVES:

The objective of this study is to determine the inheritance pattern of type-2 diabetes and make stratification for the general population risk.

MATERIALS AND METHODS:

A questionnaire was developed for o btaining the family history. Analysis of the data was carried out by using student and Chi-square tests and for stratification; the guidelines of Scheuner et al. were followed.

RESULTS:

The pattern of inheritance is the male sex specific (χ² =13.44). The mean age of onset of diabetes in parents was 58.61 ± 2.94 and in offspring 46.75 ± 2.54. In all 47.22 ± 11.53% families were found in high risk and 31.94 ± 10.77% in the moderate risk category. In female diabetics, the onset was in the age range of 41-60 years.

CONCLUSION:

We found a high-risk of diabetes and familial clustering in successive generations of Brahmins with prominent male sex specificity. In females onset of diabetes was coinciding with the period around menopause.