Variance In Liability Research Articles

Genome-wide study of half a million individuals with major depression identifies 697 independent associations, infers causal neuronal subtypes and biological targets for novel pharmacotherapies.

In a genome-wide association study (GWAS) of 685,808 individuals with major depression (MD) and 4,364,225 controls from 29 countries and across diverse and admixed ancestries, we identify 697 independent associations at 636 genetic loci, 293 of which are novel. Using fine-mapping and functional genomic datasets, we find 308 high-confidence gene associations and enrichment of postsynaptic density and receptor clustering. Leveraging new single-cell gene expression data, we conducted a causal neural cell type enrichment analysis that implicated excitatory and inhibitory midbrain and forebrain neurons, peptidergic neurons, and medium spiny neurons in MD. Critically, our findings are enriched for the targets of antidepressants and provide potential antidepressant repurposing opportunities (e.g., pregabalin and modafinil). Polygenic scores (PGS) from European ancestries explained up to 5.7% of the variance in liability to MD in European samples and PGS trained using either European or multi-ancestry data significantly predicted case control status across all four diverse ancestries. These findings represent a major advance in our understanding of MD across global populations. We provide evidence that MD GWAS reveals known and novel biological targets that may be used to target and develop pharmacotherapies addressing the considerable unmet need for effective treatment.

Genetic and Phenotypic Features of Schizophrenia in the UK Biobank

Large-scale biobanks provide important opportunities for mental health research, but selection biases raise questions regarding the comparability of individuals with those in clinical research settings. To compare the genetic liability to psychiatric disorders in individuals with schizophrenia in the UK Biobank with individuals in the Psychiatric Genomics Consortium (PGC) and to compare genetic liability and phenotypic features with participants recruited from clinical settings. This cross-sectional study included participants from the population-based UK Biobank and schizophrenia samples recruited from clinical settings (CLOZUK, CardiffCOGS, Cardiff F-Series, and Cardiff Affected Sib-Pairs). Data were collected between January 1993 and July 2021. Data analysis was conducted between July 2021 and June 2023. A genome-wide association study of UK Biobank schizophrenia case-control status was conducted, and the results were compared with those from the PGC via genetic correlations. To test for differences with the clinical samples, polygenic risk scores (PRS) were calculated for schizophrenia, bipolar disorder, depression, and intelligence using PRS-CS. PRS and phenotypic comparisons were conducted using pairwise logistic regressions. The proportions of individuals with copy number variants associated with schizophrenia were compared using Firth logistic regression. The sample of 517 375 participants included 1438 UK Biobank participants with schizophrenia (550 [38.2%] female; mean [SD] age, 54.7 [8.3] years), 499 475 UK Biobank controls (271 884 [54.4%] female; mean [SD] age, 56.5 [8.1] years), and 4 schizophrenia research samples (4758 [28.9%] female; mean [SD] age, 38.2 [21.0] years). Liability to schizophrenia in UK Biobank was highly correlated with the latest genome-wide association study from the PGC (genetic correlation, 0.98; SE, 0.18) and showed the expected patterns of correlations with other psychiatric disorders. The schizophrenia PRS explained 6.8% of the variance in liability for schizophrenia case status in UK Biobank. UK Biobank participants with schizophrenia had significantly lower schizophrenia PRS than 3 of the clinically ascertained samples and significantly lower rates of schizophrenia-associated copy number variants than the CLOZUK sample. UK Biobank participants with schizophrenia had higher educational attainment and employment rates than the clinically ascertained schizophrenia samples, lower rates of smoking, and a later age of onset of psychosis. Individuals with schizophrenia in the UK Biobank, and likely other volunteer-based biobanks, represent those less severely affected. Their inclusion in wider studies should enhance the representation of the full spectrum of illness severity.

A study of state-wise variation in liabilities and assets of district centre Co-Operative Banks in India

District Central Co-operative Bank provides capital to primary agricultural credit societies and accepts the deposits form registered and non registered members of the bank. This bank also control on all credit societies investment, liabilities and assets. It plays a significant role between state co-operative bank and primary societies. This study analysis the stat-wise comparison of liabilities and assets of district centre co-operative banks in India. Gujrat, Andhrapradesh and Tamilnadu are the states where found more fluctuation in the data of liabilities and assets of DCCBs. Thus, it seems that there is difference between banks regarding their capital and number of branches in the district. This variation is calculated by analysis of variance techniques.

Heritability and environmental influences on the onset of aortic valve sclerosis: a twin population study

Abstract Background Aortic valve sclerosis (AVSc) is the earliest manifestation of a life-threatening cardiovascular disorder, namely aortic valve stenosis (AS). AVSc is also recognized as a red flag linked to worse cardiovascular outcomes in high-risk coronary artery disease patients. However, the genetic background of AVSc is still unknown. Purpose To examine whether the heritability and environmental contributions play a role in the onset of AVSc using a sample of Italian twins. Methods The present study is based on the classical twin design. Twins, aged 50 to 70 years, already enrolled in the Italian Twin Register, were contacted and invited to undergo a clinical, echocardiographic, and complete carotid artery ultrasound examination at the our Center, between July 2017 and December 2021. The presence of AVSc was recognized as non-uniform thickening with or without spotty calcified areas of the aortic valve leaflets without a significant transvalvular gradient (maximum aortic velocity <2.5 m/s). Twin zygosity was assessed through a questionnaire on physical similarity during childhood, known to be ∼95% accurate. Tetrachoric twin correlations by zygosity were estimated with Mx Software using liability threshold saturated models and incorporating age as a covariate. Liability-threshold structural equation modelling was performed to decompose the phenotypic variance into contributions due to additive genetic (A), common environmental (C), and unique environmental (E) effects. Results A total of 216 adult twins (66 monozygotic, MZ and 42 dizygotic pairs, DZ; mean age 59.9±6.2) were enrolled in the study. The estimated prevalence rate of AVSc in the total sample was 29.2%. As significant sex differences were detected (males 45.2% and females 22.7%, p<0.01), the additional twin analyses were performed as intra-sex analyses. Females showed a greater tetrachoric correlation in MZ twins (r=0.37) compared to DZ twins (r=0.23), suggesting the existence of a genetic influence. Genetic factors, under the best (AE) model, accounted for 38% of the variance in liability to AVSc with the remaining contribution due to unique environmental influences (E = 62%). The contribution of the common environment (C) to the goodness of fit was negligible. The male group was too small for statistical calculation. Conclusion To our knowledge, the present study is the first to document the involvement of genetic factors in the development of AVSc. Our data also warrant further studies to both validate the findings obtained and to better explore the heritability of AVSc. Furthermore, our results provide a first evidence that an echocardiographic screening in individuals with relatives affected by AVSc has a scientific rational basis. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Italian Ministry of Health

Influence of Age and Genetic Background on Ethanol Intake and Behavioral Response Following Ethanol Consumption and During Abstinence in a Model of Alcohol Abuse.

Genetic background and age at first exposure have been identified as critical variables that contribute to individual vulnerability to drug addiction. Evidence shows that genetic factors may account for 40–70% of the variance in liability to addiction. Alcohol consumption by young people, especially in the form of binge-drinking, is becoming an alarming phenomenon predictive of future problems with drinking. Thus, the literature indicates the need to better understand the influence of age and genetic background on the development of alcohol dependence. To this aim, the inbred rat strains Lewis (LEW, addiction prone) and Fischer 344 (F344, addiction resistant) were used as a model of genetic vulnerability to addiction and compared with the outbred strain Sprague-Dawley (SD) in a two-bottle choice paradigm as a model of alcohol abuse. During a 9-week period, adolescent and adult male rats of the three strains were intermittently exposed to ethanol (20%) and water during three 24-h sessions/week. Adult and adolescent SD and LEW rats escalated their alcohol intake over time reaching at stable levels, while F344 rats did not escalate their intake, regardless of age at drinking onset. Among adolescents, only F344 rats consumed a higher total amount of ethanol than adults, although only SD and LEW rats escalated their intake. Adult LEW rats, albeit having a lower ethanol consumption as compared to SD rats but greater than F344, showed a more compulsive intake, consuming higher amounts of ethanol during the first hour of exposure, reaching a higher degree of ethanol preference when start drinking as adolescents. Behavioral analysis during the first hour of ethanol consumption revealed significant strain differences, among which noticeable the lack of sedative effect in the LEW strain, at variance with F344 and SD strains, and highest indices of withdrawal (most notable jumping) in LEW rats during the first hour of abstinence days. The present results underscore the importance of individual genetic background and early onset of alcohol use in the progression toward abuse and development of alcohol addiction.

Boosting Schizophrenia Genetics by Utilizing Genetic Overlap With Brain Morphology

BackgroundSchizophrenia is a complex polygenic disorder with subtle, distributed abnormalities in brain morphology. There are indications of shared genetic architecture between schizophrenia and brain measures despite low genetic correlations. Through the use of analytical methods that allow for mixed directions of effects, this overlap may be leveraged to improve our understanding of underlying mechanisms of schizophrenia and enrich polygenic risk prediction outcome. MethodsWe ran a multivariate genome-wide analysis of 175 brain morphology measures using data from 33,735 participants of the UK Biobank and analyzed the results in a conditional false discovery rate together with schizophrenia genome-wide association study summary statistics of the Psychiatric Genomics Consortium (PGC) Wave 3. We subsequently created a pleiotropy-enriched polygenic score based on the loci identified through the conditional false discovery rate approach and used this to predict schizophrenia in a nonoverlapping sample of 743 individuals with schizophrenia and 1074 healthy controls. ResultsWe found that 20% of the loci and 50% of the genes significantly associated with schizophrenia were also associated with brain morphology. The conditional false discovery rate analysis identified 428 loci, including 267 novel loci, significantly associated with brain-linked schizophrenia risk, with functional annotation indicating high relevance for brain tissue. The pleiotropy-enriched polygenic score explained more variance in liability than conventional polygenic scores across several scenarios. ConclusionsOur results indicate strong genetic overlap between schizophrenia and brain morphology with mixed directions of effect. The results also illustrate the potential of exploiting polygenetic overlap between brain morphology and mental disorders to boost discovery of brain tissue–specific genetic variants and its use in polygenic risk frameworks.

Genome-wide association study of febrile seizures implicates fever response and neuronal excitability genes.

Febrile seizures represent the most common type of pathological brain activity in young children and are influenced by genetic, environmental and developmental factors. In a minority of cases, febrile seizures precede later development of epilepsy.We conducted a genome-wide association study of febrile seizures in 7635 cases and 83 966 controls identifying and replicating seven new loci, all with P < 5 × 10−10.Variants at two loci were functionally related to altered expression of the fever response genes PTGER3 and IL10, and four other loci harboured genes (BSN, ERC2, GABRG2, HERC1) influencing neuronal excitability by regulating neurotransmitter release and binding, vesicular transport or membrane trafficking at the synapse. Four previously reported loci (SCN1A, SCN2A, ANO3 and 12q21.33) were all confirmed. Collectively, the seven novel and four previously reported loci explained 2.8% of the variance in liability to febrile seizures, and the single nucleotide polymorphism heritability based on all common autosomal single nucleotide polymorphisms was 10.8%. GABRG2, SCN1A and SCN2A are well-established epilepsy genes and, overall, we found positive genetic correlations with epilepsies (rg = 0.39, P = 1.68 × 10−4). Further, we found that higher polygenic risk scores for febrile seizures were associated with epilepsy and with history of hospital admission for febrile seizures. Finally, we found that polygenic risk of febrile seizures was lower in febrile seizure patients with neuropsychiatric disease compared to febrile seizure patients in a general population sample.In conclusion, this largest genetic investigation of febrile seizures to date implicates central fever response genes as well as genes affecting neuronal excitability, including several known epilepsy genes. Further functional and genetic studies based on these findings will provide important insights into the complex pathophysiological processes of seizures with and without fever.

Familial risk and heritability of intellectual disability: a population-based cohort study in Sweden.

Intellectual disability (ID) aggregates in families, but factors affecting individual risk and heritability estimates remain unknown. A population-based family cohort study of 4,165,785 individuals born 1973-2013 in Sweden, including 37,787 ID individuals and their relatives. The relative risks (RR) of ID with 95% confidence intervals (95% CI) were obtained from stratified Cox proportional-hazards models. Relatives of ID individuals were compared to relatives of unaffected individuals. Structural equationmodeling was used to estimate heritability. Relatives of ID individuals were at increased risk of ID compared to individuals with unaffected relatives. The RR of ID among relatives increased proportionally to the degree of genetic relatedness with ID probands; 256.70(95% CI 161.30-408.53) for monozygotic twins, 16.47(13.32-20.38) for parents, 14.88(12.19-18.16) for children, 7.04(4.67-10.61) for dizygotic twins, 8.38(7.97-8.83) for full siblings, 4.56(4.02-5.16) for maternal, 2.90(2.49-3.37) for paternal half-siblings, 3.03(2.61-3.50) for nephews/nieces, 2.84(2.45-3.29) for uncles/aunts, and 2.04(1.91-2.20) for cousins. Lower RRs were observed for siblings of probands with chromosomal abnormalities (RR 5.53, 4.74-6.46) and more severe ID (mild RR 9.15, 8.55-9.78, moderate RR 8.13, 7.28-9.08, severe RR 6.80, 5.74-8.07, and profound RR 5.88, 4.52-7.65). Male sex of relative and maternal line of relationship with proband was related to higher risk (RR 1.33, 1.25-1.41 for brothers vs. sisters and RR 1.49, 1.34-1.68 for maternal vs. paternal half-siblings). ID was substantially heritable with 0.95(95% CI 0.93-0.98) of the variance in liability attributed to genetic influences. The risk estimates will benefit researchers, clinicians, families in understanding the risk of ID in the family and the whole population. The higher risk of ID related to male sex and maternal linage will be of value for planning and interpreting etiological studies in ID.

A Comparison of Ten Polygenic Score Methods for Psychiatric Disorders Applied Across Multiple Cohorts

BackgroundPolygenic scores (PGSs), which assess the genetic risk of individuals for a disease, are calculated as a weighted count of risk alleles identified in genome-wide association studies. PGS methods differ in which DNA variants are included and the weights assigned to them; some require an independent tuning sample to help inform these choices. PGSs are evaluated in independent target cohorts with known disease status. Variability between target cohorts is observed in applications to real data sets, which could reflect a number of factors, e.g., phenotype definition or technical factors. MethodsThe Psychiatric Genomics Consortium Working Groups for schizophrenia and major depressive disorder bring together many independently collected case-control cohorts. We used these resources (31,328 schizophrenia cases, 41,191 controls; 248,750 major depressive disorder cases, 563,184 controls) in repeated application of leave-one-cohort-out meta-analyses, each used to calculate and evaluate PGS in the left-out (target) cohort. Ten PGS methods (the baseline PC+T method and 9 methods that model genetic architecture more formally: SBLUP, LDpred2-Inf, LDpred-funct, LDpred2, Lassosum, PRS-CS, PRS-CS-auto, SBayesR, MegaPRS) were compared. ResultsCompared with PC+T, the other 9 methods gave higher prediction statistics, MegaPRS, LDPred2, and SBayesR significantly so, explaining up to 9.2% variance in liability for schizophrenia across 30 target cohorts, an increase of 44%. For major depressive disorder across 26 target cohorts, these statistics were 3.5% and 59%, respectively. ConclusionsAlthough the methods that more formally model genetic architecture have similar performance, MegaPRS, LDpred2, and SBayesR rank highest in most comparisons and are recommended in applications to psychiatric disorders.

Correlates and genetics of self-reported sleep and awake bruxism in a nationwide twin cohort.

Sleep bruxism (SB) and awake bruxism (AB) have been considered different entities, although co-occurrence between them has been shown. While genetic factors have a marked influence on phenotypic variance in liability to SB, this remains unclear for AB. To examine the degree of co-occurrence of SB and AB, and whether they have common correlates and also twin similarity of SB and AB bruxism traits by zygosity and sex. A questionnaire was mailed to all twins born 1945-1957 in Finland in 2012 (n=11766). Age and sex adjusted logistic regression models were used. Twin similarity was assessed using polychoric correlations, and crosstwin-crosstrait correlations were computed. The response rate was 72% (n=8410). Any SB was reported by 14.8% and≥3 nights weekly by 5.0%. Percentages for any AB were 18.4% and 6.3%, respectively. There was substantial co-occurrence (29.5%) between SB and AB, and several shared correlates were found. For SB, the polychoric intra-class correlation was 0.366 in monozygotic (MZ) and 0.200 in dizygotic (DZ) pairs, without gender difference. A twofold crosstwin-crosstrait correlation was observed in MZ twins compared to DZ twins. The risk factor profiles of SB and AB were largely but not entirely similar. The higher correlation in MZ than in DZ pairs suggests the influence of genetic factors on both SB and AB. The higher crosstwin-crosstrait correlation in MZ than in DZ pairs suggests some degree of genetic influences shared by SB and AB.

43 - GENOME-WIDE ASSOCIATION ANALYSES IDENTIFY 44 RISK VARIANTS AND REFINE THE GENETIC ARCHITECTURE OF MAJOR DEPRESSIVE DISORDER

Background Major Depressive Disorder (MDD) is a notably complex illness with a lifetime prevalence of 14%. It is often chronic or recurrent and is thus accompanied by considerable morbidity, excess mortality, substantial costs, and heightened risk of suicide. MDD is a major cause of disability worldwide. Twin studies attribute ~40% of the variation in liability to MDD to additive genetic effects, and may be greater for recurrent, early-onset, and postpartum MDD. GWA studies of MDD have had notable difficulties in identifying loci. Previous findings suggest that an appropriately designed study should identify susceptibility loci. Methods We conducted a Genome-Wide Association (GWA) meta-analysis in 130,664 MDD cases and 330,470 controls. We used the standard GWA mega/meta-analysis methods of the core PGC quality control, imputation, and analysis pipeline (i.e., ricopili) Results We identified 44 independent loci that met criteria for statistical significance. We can make a strong case for the identification of RBFOX1 and NEGR1. The genetic findings were associated with clinical features of MDD, and implicated prefrontal and anterior cingulate cortex in the pathophysiology of MDD (regions exhibiting anatomical differences in MDD cases vs controls). Genes that are targets of antidepressant medications were strongly enriched for MDD association signals (P=8.5e-10), suggesting the relevance of these findings for improved pharmacotherapy of MDD. Sets of genes involved in gene splicing and in creating isoforms were also enriched for smaller MDD GWA P-values, and these gene sets have also been implicated in schizophrenia and autism. Genetic risk for MDD was correlated with that for many adult and childhood onset psychiatric disorders. Our analyses suggested important relations of genetic risk for MDD with educational attainment, body mass, and schizophrenia: the genetic basis of lower educational attainment and higher body mass were putatively causal for MDD whereas MDD and schizophrenia reflected a partly shared biological etiology. Discussion We present extensive analyses of these results which provide new insights into the nature of MDD. All humans carry lesser or greater numbers of genetic risk factors for MDD, and a continuous measure of risk underlies the observed clinical phenotype. MDD is not a distinct entity that neatly demarcates normalcy from pathology but rather a useful clinical construct associated with a range of adverse outcomes and the end result of a complex process of intertwined genetic and environmental effects. These findings help refine and define the fundamental basis of MDD.

Common genetic variation in the autoimmune regulator (AIRE) locus is associated with autoimmune Addison\u2019s disease in Sweden

Autoimmune Addison’s disease (AAD) is the predominating cause of primary adrenal failure. Despite its high heritability, the rarity of disease has long made candidate-gene studies the only feasible methodology for genetic studies. Here we conducted a comprehensive reinvestigation of suggested AAD risk loci and more than 1800 candidate genes with associated regulatory elements in 479 patients with AAD and 2394 controls. Our analysis enabled us to replicate many risk variants, but several other previously suggested risk variants failed confirmation. By exploring the full set of 1800 candidate genes, we further identified common variation in the autoimmune regulator (AIRE) as a novel risk locus associated to sporadic AAD in our study. Our findings not only confirm that multiple loci are associated with disease risk, but also show to what extent the multiple risk loci jointly associate to AAD. In total, risk loci discovered to date only explain about 7% of variance in liability to AAD in our study population.

NLRP genes and their role in preeclampsia and multi-locus imprinting disorders.

Preeclampsia (PE) affects 2-5% of all pregnancies. It is a multifactorial disease, but it has been estimated that 35% of the variance in liability of PE are attributable to maternal genetic effects and 20% to fetal genetic effects. PE has also been reported in women delivering children with Beckwith-Wiedemann syndrome (BWS, OMIM 130650), a disorder associated with aberrant methylation at genomically imprinted loci. Among others, members of the NLRP gene family are involved in the etiology of imprinting defects. Thus, a functional link between PE, NLRP gene mutations and aberrant imprinting can be assumed. Therefore we analyzed a cohort of 47 PE patients for NLRP gene mutations by next generation sequencing. In 25 fetuses where DNA was available we determined the methylation status at the imprinted locus. With the exception of one woman heterozygous for a missense variant in the NLRP7 gene (NM_001127255.1(NLRP7):c.542G>C) we could not identify further carriers, in the fetal DNA normal methylation patterns were observed. Thus, our negative screening results in a well-defined cohort indicate that NLRP mutations are not a relevant cause of PE, though strong evidence for a functional link between NLRP mutations, PE and aberrant methylation exist.

Identification of biological pathways to Alzheimer's disease using polygenic scores

IntroductionSingle nucleotide polymorphisms (SNPs) contribute small increases in risk for late-onset Alzheimer's disease (LOAD). LOAD SNPs cluster around genes with similar biological functions (pathways). Polygenic risk scores (PRS) aggregate the effect of SNPs genome-wide. However, this approach has not been widely used for SNPs within specific pathways.ObjectivesWe investigated whether pathway-specific PRS were significant predictors of LOAD case/control status.MethodsWe mapped SNPs to genes within 8 pathways implicated in LOAD. For our polygenic analysis, the discovery sample comprised 13,831 LOAD cases and 29,877 controls. LOAD risk alleles for SNPs in our 8 pathways were identified at a P-value threshold of 0.5. Pathway-specific PRS were calculated in a target sample of 3332 cases and 9832 controls. The genetic data were pruned with R2 &gt; 0.2 while retaining the SNPs most significantly associated with AD. We tested whether pathway-specific PRS were associated with LOAD using logistic regression, adjusting for age, sex, country, and principal components. We report the proportion of variance in liability explained by each pathway.ResultsThe most strongly associated pathways were the immune response (NSNPs = 9304, = 5.63 × 10−19, R2 = 0.04) and hemostasis (NSNPs = 7832, P = 5.47 × 10−7, R2 = 0.015). Regulation of endocytosis, hematopoietic cell lineage, cholesterol transport, clathrin and protein folding were also significantly associated but accounted for less than 1% of the variance. With APOE excluded, all pathways remained significant except proteasome-ubiquitin activity and protein folding.ConclusionsGenetic risk for LOAD can be split into contributions from different biological pathways. These offer a means to explore disease mechanisms and to stratify patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.

A Genetic Epidemiological Mega Analysis of Smoking Initiation in Adolescents.

Previous studies in adolescents were not adequately powered to accurately disentangle genetic and environmental influences on smoking initiation (SI) across adolescence. Mega-analysis of pooled genetically informative data on SI was performed, with structural equation modeling, to test equality of prevalence and correlations across cultural backgrounds, and to estimate the significance and effect size of genetic and environmental effects according to the classical twin study, in adolescent male and female twins from same-sex and opposite-sex twin pairs (N = 19 313 pairs) between ages 10 and 19, with 76 358 longitudinal assessments between 1983 and 2007, from 11 population-based twin samples from the United States, Europe, and Australia. Although prevalences differed between samples, twin correlations did not, suggesting similar etiology of SI across developed countries. The estimate of additive genetic contributions to liability of SI increased from approximately 15% to 45% from ages 13 to 19. Correspondingly, shared environmental factors accounted for a substantial proportion of variance in liability to SI at age 13 (70%) and gradually less by age 19 (40%). Both additive genetic and shared environmental factors significantly contribute to variance in SI throughout adolescence. The present study, the largest genetic epidemiological study on SI to date, found consistent results across 11 studies for the etiology of SI. Environmental factors, especially those shared by siblings in a family, primarily influence SI variance in early adolescence, while an increasing role of genetic factors is seen at later ages, which has important implications for prevention strategies. This is the first study to find evidence of genetic factors in liability to SI at ages as young as 12. It also shows the strongest evidence to date for decay of effects of the shared environment from early adolescence to young adulthood. We found remarkable consistency of twin correlations across studies reflecting similar etiology of liability to initiate smoking across different cultures and time periods. Thus familial factors strongly contribute to individual differences in who starts to smoke with a gradual increase in the impact of genetic factors and a corresponding decrease in that of the shared environment.

A sibling based design to quantify genetic and shared environmental effects of venous thromboembolism in Sweden

IntroductionFew large studies have examined the heritability of venous thromboembolism (VTE). Moreover, twin studies have been suggested to overestimate heritability. The aim of the present study was to determine the heritability nationwide in the general Swedish population using full siblings and half-siblings. MethodsVTE was defined using the Swedish patient register. Full sibling (FS) and half-sibling (HS) pairs born 1950–1990 were obtained from the Swedish Multi-generation Register. A maximum of 5years age difference was allowed. We also required that the individuals within the pair should reside in the same household for at least 8years or not at all (0years) before the youngest turned 16. Information about sibling pair residence within the same household, small residential area, and municipality was obtained from Statistics Sweden. We assumed three potential sources of liability to VTE: additive genetic (A), shared (or common/familial) environment (C), and unique environment (E) components. ResultsTotally 881,206 FS pairs and 95,198 HS pairs were included. The full model predicted heritability for VTE with 47% for males and 40% for females. Environmental factors shared by siblings contributed to 0% of the variance in liability for both sexes, and unique environment (E) components accounted for 53% in males and 60% in females. ConclusionThe high heritability of VTE risk indicates that genetic susceptibility plays a substantial role for VTE in the Swedish general population. Overestimation of heritability from twin studies is not likely. The proportion of the variance attributable to shared familial environment factors is small.Subject codes: Genetics, epidemiology, thrombosis, cardiovascular disease, embolism

Understanding the covariation of tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms: A population-based adult twin study.

Chronic tic disorders (TD), attention-deficit/hyperactivity-disorder (ADHD), and obsessive-compulsive disorder (OCD) frequently co-occur in clinical and epidemiological samples. Family studies have found evidence of shared familial transmission between TD and OCD, whereas the familial association between these disorders and ADHD is less clear. This study aimed to investigate to what extent liability of tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms is caused by shared or distinct genetic or environmental influences, in a large population-representative sample of Swedish adult twins (n = 21,911). Tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms showed modest, but significant covariation. Model fitting suggested a latent liability factor underlying the three phenotypes. This common factor was relatively heritable, and explained significantly less of the variance of attention-deficit/hyperactivity symptom liability. The majority of genetic variance was specific rather than shared. The greatest proportion of total variance in liability of tics, attention-deficit/hyperactivity, and obsessive-compulsive symptoms was attributed to specific non-shared environmental influences. Our findings suggest that the co-occurrence of tics and obsessive-compulsive symptoms, and to a lesser extent attention-deficit/hyperactivity symptoms, can be partly explained by shared etiological influences. However, these phenotypes do not appear to be alternative expressions of the same underlying genetic liability. Further research examining sub-dimensions of these phenotypes may serve to further clarify the association between these disorders and identify more genetically homogenous symptom subtypes. © 2016 Wiley Periodicals, Inc.

Sex differences in risk and heritability estimates on primary knee osteoarthritis leading to total knee arthroplasty: a nationwide population based follow up study in Danish twins.

BackgroundSymptomatic knee osteoarthritis is a highly age and sex associated complex disease. Little is known about the causes behind this age and sex associated increase, or if genetic and environmental factors impacts differently by gender. Our study examined the risk and heritability of primary knee osteoarthritis leading to total knee arthroplasty and whether these differences were attributable to sex and age differences in heritability.MethodsAll twins of known zygosity from The Danish Twin Register alive in 1997 were examined in a nationwide population based follow-up study collecting information on all twins recorded in The Danish Knee Arthroplasty from 1997 to follow-up in 2010. Our main outcomes were the cumulative incidence, probandwise concordance rates, heritability, within pair correlations in monozygotic and dizygotic twin pairs and the genetic and environmental influence estimated in models taking into account that individuals may not have had a total knee arthroplasty at follow up.Results92,748 twins were eligible for analyses and 576 twins had a record of primary knee osteoarthritis in The Danish Knee Arthroplasty Register at follow-up comprising 358 female and 218 male twin cases. The risk increased particular after the age of 50 years displaying significant sex differences in the elderly. In the sex stratified analyses a discrete genetic component was found in females, but in males no genetic component could be detected. In both genders common and unique environmental factors were highly significant. In the sex-adjusted analysis an additive genetic component of 18 % (0; 62), a shared environmental component of 61 % (25; 97) and an individual environmental component of 21 % (6; 36) accounted for the variation in liability to primary total knee arthroplasty.ConclusionThe risk of primary total knee arthroplasty increases significantly after the age of 50 years, in particular in females, displaying significant sex differences in the elderly. After sex-adjustment 82 % of the variation in liability to primary total knee arthroplasty was attributable to common and unique environmental factors; the remaining 18 % of this variation was attributable to additive genetic factors indicating a pivotal impact of environmental factors on this disease.

Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction.

Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40–60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant deviations in reward and motivational functions.

The Heritability of Breast Cancer among Women in the Nordic Twin Study of Cancer.

Family history is an established risk factor for breast cancer. Although some important genetic factors have been identified, the extent to which familial risk can be attributed to genetic factors versus common environment remains unclear. We estimated the familial concordance and heritability of breast cancer among 21,054 monozygotic and 30,939 dizygotic female twin pairs from the Nordic Twin Study of Cancer, the largest twin study of cancer in the world. We accounted for left-censoring, right-censoring, as well as the competing risk of death. From 1943 through 2010, 3,933 twins were diagnosed with breast cancer. The cumulative lifetime incidence of breast cancer taking competing risk of death into account was 8.1% for both zygosities, although the cumulative risk for twins whose co-twins had breast cancer was 28% among monozygotic and 20% among dizygotic twins. The heritability of liability to breast cancer was 31% [95% confidence interval (CI), 10%-51%] and the common environmental component was 16% (95% CI, 10%-32%). For premenopausal breast cancer these estimates were 27% and 12%, respectively, and for postmenopausal breast cancer 22% and 16%, respectively. The relative contributions of genetic and environmental factors were constant between ages 50 and 96. Our results are compatible with the Peto-Mack hypothesis. Our findings indicate that familial factors explain almost half of the variation in liability to develop breast cancer, and results were similar for pre- and postmenopausal breast cancer We estimate heritability of breast cancer, taking until now ignored sources of bias into account.