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Substance use disorders (SUDs) are prevalent and result in an array of negative consequences. They are influenced by genetic factors (h2 = ~50%). Recent years have brought substantial progress in our understanding of the genetic etiology of SUDs and related traits. The present review covers the current state of the field for SUD genetics, including the epidemiology and genetic epidemiology of SUDs, findings from the first-generation of SUD genome-wide association studies (GWAS), cautions about translating GWAS findings to clinical settings, and suggested prioritizations for the next wave of SUD genetics efforts. Recent advances in SUD genetics have been facilitated by the assembly of large GWAS samples, and the development of state-of-the-art methods modeling the aggregate effect of genome-wide variation. These advances have confirmed that SUDs are highly polygenic with many variants across the genome conferring risk, the vast majority of which are of small effect. Downstream analyses have enabled finer resolution of the genetic architecture of SUDs and revealed insights into their genetic relationship with other psychiatric disorders. Recent efforts have also prioritized a closer examination of GWAS findings that have suggested non-uniform genetic influences across measures of substance use (e.g. consumption) and problematic use (e.g. SUD). Additional highlights from recent SUD GWAS include the robust confirmation of loci in alcohol metabolizing genes (e.g. ADH1B and ALDH2) affecting alcohol-related traits, and loci within the CHRNA5-CHRNA3-CHRNB4 gene cluster influencing nicotine-related traits. Similar successes are expected for cannabis, opioid, and cocaine use disorders as sample sizes approach those assembled for alcohol and nicotine.
Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation.
Using data from 9,421 individuals aged 8–21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation.
Externalizing was heritable (h2 = 0.46, p = 1 × 10−6), but not anxious-misery (h2 = 0.09, p = 0.183), fear (h2 = 0.04, p = 0.337), psychosis-spectrum (h2 = 0.00, p = 0.494), or general psychopathology (h2 = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρg = −0.412, p = 0.004), verbal reasoning (ρg = −0.485, p = 0.001), spatial reasoning (ρg = −0.426, p = 0.010), motor speed (ρg = 0.659, p = 1x10−4), verbal knowledge (ρg = −0.314, p = 0.002), and general cognitive ability (g)(ρg = −0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γg = −0.146, p = 0.004) and increasing environmental variance (γe = 0.059, p = 0.009) on externalizing.
Cognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.
The present study aimed to determine the genetic and environmental etiology of the association between childhood negative emotionality (NE) and hyperactivity/inattention problems (HIP) using South Korean elementary school twins (mean age = 10.19 years, SD = 1.79 years). Telephone interviews were given to mothers of 919 twins (229 monozygotic males: 112 pairs and 5 individuals; 148 dizygotic males: 73 pairs and 2 individuals; 180 monozygotic females: 87 pairs and 6 individuals; 103 dizygotic females: 50 pairs and 3 individuals; 259 opposite-sex dizygotic twins: 127 pairs and 5 individuals) to assess their children’s NE and HIP. Consistent with prior studies, the phenotypic correlation between NE and the HIP was moderate (r = .29; 95% CI = .24, .34). Model-fitting analysis revealed that additive genetic and nonshared environmental influences on NE were .45 (95% CI [.34, .54]) and .55 (95% CI [.46, .66]), respectively, and that additive and nonadditive genetic, and nonshared environmental influences on HIP were .08 (95% CI [.03, .26]), .41 (95% CI [.21, .51]) and .51 (95% CI = .42, .61), respectively. In addition, the additive genetic correlation between NE and HIP was 1.0 (95% CI [.52, 1.00]), indicating that additive genetic factors are entirely shared between the two phenotypes. Nonadditive genetic influences were unique to HIP and not responsible for the NE-HIP association. Nonshared environmental correlation was significant but modest (re = .18, 95% CI [.06, .30]).
Twin studies of physical exercise for Asian twins are sparse. This study aimed to examine genetic and environmental influences on frequency of vigorous exercise (FVE) in South Korean twins, with a special emphasis on sex effects. Telephone interviews on FVE were administered to 1757 twins (mean age = 19.05 years, SD = 3.01 years). Tetrachoric correlations were significantly different between monozygotic (MZ) and dizygotic (DZ) twins in males (.40 vs. .12), but they were similar in females (.44 vs. .45), suggesting the importance of genetic factors in FVE in males and that of common environmental factors in females. A scalar sex-limitation model incorporating age as a modifier was applied to data. The results revealed that genetic, common and individual environmental influences did not vary significantly with age, but differed across two sexes, confirming twin correlational analyses. In the best-fitting model, additive genetic and individual environmental influences on FVE were, respectively, .35 (95% CI [.26, .39]) and .65 (95% CI [.61, .74]) in males, and common and individual environmental influences were, respectively, .45 (95% CI [.35, .53]) and .55 (95% CI [.47, .65]) in females. These results contrasted starkly with recent findings from a large sample of Chinese adult twins (age >18 years), in which most variance (≥95%) of vigorous physical activity was attributable to common environmental influences in both sexes. Replications in other Asian samples are clearly needed.
Twin studies function as natural experiments that reveal political ideology’s substantial genetic roots, but how does that comport with research showing a largely nonideological public? This study integrates two important literatures and tests whether political sophistication – itself heritable – provides an “enriched environment” for genetic predispositions to actualize in political attitudes. Estimates from the Minnesota Twin Study show that sociopolitical conservatism is extraordinarily heritable (74%) for the most informed fifth of the public – much more so than population-level results (57%) – but with much lower heritability (29%) for the public’s bottom half. This heterogeneity is clearest in the Wilson–Patterson (W-P) index, with similar patterns for individual index items, an ideological constraint measure, and ideological identification. The results resolve tensions between two key fields by showing that political knowledge facilitates the expression of genetic predispositions in mass politics.
Anxiety disorders are among the most common psychiatric disorders worldwide. They often onset early in life, with symptoms and consequences that can persist for decades. This makes anxiety disorders some of the most debilitating and costly disorders of our time. Although much is known about the synaptic and circuit mechanisms of fear and anxiety, research on the underlying genetics has lagged behind that of other psychiatric disorders. However, alongside the formation of the Psychiatric Genomic Consortium Anxiety workgroup, progress is rapidly advancing, offering opportunities for future research.
Here we review current knowledge about the genetics of anxiety across the lifespan from genetically informative designs (i.e. twin studies and molecular genetics). We include studies of specific anxiety disorders (e.g. panic disorder, generalised anxiety disorder) as well as those using dimensional measures of trait anxiety. We particularly address findings from large-scale genome-wide association studies and show how such discoveries may provide opportunities for translation into improved or new therapeutics for affected individuals. Finally, we describe how discoveries in anxiety genetics open the door to numerous new research possibilities, such as the investigation of specific gene–environment interactions and the disentangling of causal associations with related traits and disorders.
We discuss how the field of anxiety genetics is expected to move forward. In addition to the obvious need for larger sample sizes in genome-wide studies, we highlight the need for studies among young people, focusing on specific underlying dimensional traits or components of anxiety.
Our objective was to evaluate the genetic merit of Holstein cattle population in southern Brazil in response to variations in the regional temperature by analyzing the genotype by environment interaction using reaction norms. Fat yield (FY) and protein yield (PY) data of 67 360 primiparous cows were obtained from the database of the Paraná Holstein Breeders Association, Brazil (APCBRH). The regional average annual temperature was used as the environmental variable. A random regression model was adopted applying mixed models with Restricted Maximum Likelihood (REML) algorithm using WOMBAT software. The genetic merit of the 15 most representative bulls, depending on the temperature gradient, was evaluated. Heritability ranged from 0.21 to 0.27 for FY and from 0.14 to 0.20 for PY. The genetic correlation observed among the environmental gradients proved to be higher than 0.80 for both traits. Slight reranking of bulls for both traits was detected, demonstrating that non-relevant genotype by environment interaction for FY and PY were observed. Consequently, no inclusion of the temperature effect in the model of genetic evaluation in southern Brazilian Holstein breed is required.
Our objective was to determine the content of the bioactive protein osteopontin (OPN) in bovine milk and identify factors influencing its concentration. OPN is expressed in many tissues and body fluids, with by far the highest concentrations in milk. OPN plays a role in immunological and developmental processes and it has been associated with several milk production traits and lactation persistency in cows. In the present study, we report the development of an enzyme linked immunosorbent assay (ELISA) for measurement of OPN in bovine milk. The method was used to determine the concentration of OPN in milk from 661 individual Danish Holstein cows. The median OPN level was determined to 21.9 mg/l with a pronounced level of individual variation ranging from 0.4 mg/l to 67.8 mg/l. Breeding for increased OPN in cow's milk is of significant interest, however, the heritability of OPN in milk was found to be relatively low, with an estimated value of 0.19 in the current dataset. The variation explained by the herd was also found to be low suggesting that OPN levels are not affected by farm management or feeding. Interestingly, the concentration of OPN was found to increase with days in milk and to decrease with parity.
A healthy diet is associated with the improvement or maintenance of health parameters, and several indices have been proposed to assess diet quality comprehensively. Twin studies have found that some specific foods, nutrients and food patterns have a heritable component; however, the heritability of overall dietary intake has not yet been estimated. Here, we compute heritability estimates of the nine most common dietary indices utilized in nutritional epidemiology. We analyzed 2590 female twins from TwinsUK (653 monozygotic [MZ] and 642 dizygotic [DZ] pairs) who completed a 131-item food frequency questionnaire (FFQ). Heritability estimates were computed using structural equation models (SEM) adjusting for body mass index (BMI), smoking status, Index of Multiple Deprivation (IMD), physical activity, menopausal status, energy and alcohol intake. The AE model was the best-fitting model for most of the analyzed dietary scores (seven out of nine), with heritability estimates ranging from 10.1% (95% CI [.02, .18]) for the Dietary Reference Values (DRV) to 42.7% (95% CI [.36, .49]) for the Alternative Healthy Eating Index (A-HEI). The ACE model was the best-fitting model for the Healthy Diet Indicator (HDI) and Healthy Eating Index 2010 (HEI-2010) with heritability estimates of 5.4% (95% CI [−.17, .28]) and 25.4% (95% CI [.05, .46]), respectively. Here, we find that all analyzed dietary indices have a heritable component, suggesting that there is a genetic predisposition regulating what you eat. Future studies should explore genes underlying dietary indices to further understand the genetic disposition toward diet-related health parameters.
Susceptibility to infection such as SARS-CoV-2 may be influenced by host genotype. TwinsUK volunteers (n = 3261) completing the C-19 COVID-19 symptom tracker app allowed classical twin studies of COVID-19 symptoms, including predicted COVID-19, a symptom-based algorithm to predict true infection, derived from app users tested for SARS-CoV-2. We found heritability of 49% (32−64%) for delirium; 34% (20−47%) for diarrhea; 31% (8−52%) for fatigue; 19% (0−38%) for anosmia; 46% (31−60%) for skipped meals and 31% (11−48%) for predicted COVID-19. Heritability estimates were not affected by cohabiting or by social deprivation. The results suggest the importance of host genetics in the risk of clinical manifestations of COVID-19 and provide grounds for planning genome-wide association studies to establish specific genes involved in viral infectivity and the host immune response.
Genomic variation exists in cattle that affects their susceptibility to the complex of pathogens responsible for bovine respiratory disease (BRD). Heritability estimates and genome-wide association analyses (GWAA) support the role of host genomic variation in BRD susceptibility. Heritability estimates for BRD susceptibility range from 0.02 to 0.29 depending on the population, the definition of the disease, and the accuracy of diagnosis. GWAA have identified genomic regions (loci) associated with BRD in beef and dairy cattle based on a variety of BRD diagnostic criteria. National standards need to be developed for BRD diagnostics and reporting to facilitate selection. Commercial genotyping is available to predict BRD susceptibility in dairy cattle and for the selection of replacement animals. Disease pathogen profiles vary by region and can result in genetic heterogeneity where different loci are important for susceptibility to different BRD pathogens. Although the identification of the BRD pathogens may not be critical for treatment, it is of paramount importance in identifying loci that render cattle susceptible to the disease. Identification of loci associated with host susceptibility to BRD provides a foundation for genomic selection to reduce disease and opens the possibilities to a better understanding of how the host defends itself.
Breeding for resistance to biotic stress and higher yield is a continuous process. Thus, the identification of desirable parents with good combining ability and nature of gene action for the target trait is of utmost importance. Hence, in this present investigation, 10 lines and three testers of Okra were crossed in line × tester mating design to generate 30 testcross progenies and their evaluation along with parents and check in a randomized complete block design with three replications. To depict the true picture of genetic variation among the parental genotypes, molecular diversity analysis was also carried out using genomic-simple sequence repeats before crossing to ascertain that sufficient variability is present among the parents. The molecular analysis grouped the parental genotypes into four clusters (I–IV). The analysis of variance revealed that all the treatments were significant for most of the traits. The combining ability analysis suggested Pusa A-4 as the best general combiner for earliness, Pusa Bhindi-5 for high yield, and DOV-92 for fruit length, plant height, yield per plant, and coefficient of infection for Yellow Vein Mosaic Virus Disease resistance. Similarly, the specific combining ability analysis suggested that the cross combinations DOV-92 × Pusa Bhindi-5 followed by DOV-92 × Pusa A-4 and DOV-92 × Pusa Sawani exhibit high economic heterosis for yield per plant as well as for disease resistance. Finally, estimation of the degree of dominance and predictability ratio was also worked out which indicated the prevalence of non-additive gene action for most of the traits pointing towards sufficient scope for heterosis breeding in Okra.
Plant height in chickpea is a multivariate, dynamic trait, and shows differences in growth rate at different stages of plant development in different genotypes. In the majority of plant-breeding experiments, the phenotypic data on a quantitative trait measured at a fixed time point (generally at maturity) are used for quantitative trait loci (QTL) mapping. However, this method can result in missing important/major QTLs which are expressed at different time points and are not expressed at maturity. In the current study, using a set of 49 desi chickpea genotypes sown at three different durations for two successive years, we observed that heritability for plant height was highest at the 2 month stage in the normal sown trial, and at the 1 month stage in late-sown trials. However, heritability drastically declines at maturity, particularly due to heat stress with an increase in temperatures during the growing period. In the association analysis, it was also observed that almost all the marker–trait associations (MTAs) identified using endpoint phenotypes were identified using data obtained at different intervals. In addition, some novel and stage-specific MTAs were identified using phenotypic data recorded at monthly intervals. The results highlight the importance of multistage phenotyping for dynamic traits like plant height in germplasm characterization programmes.
There is a common misconception that our genomes - all unique, except for those in identical twins - have the upper hand in controlling our destiny. The latest genetic discoveries, however, do not support that view. Although genetic variation does influence differences in various human behaviours to a greater or lesser degree, most of the time this does not undermine our genuine free will. Genetic determinism comes into play only in various medical conditions, notably some psychiatric syndromes. Denis Alexander here demonstrates that we are not slaves to our genes. He shows how a predisposition to behave in certain ways is influenced at a molecular level by particular genes. Yet a far greater influence on our behaviours is our world-views that lie beyond science - and that have an impact on how we think the latest genetic discoveries should, or should not, be applied. Written in an engaging style, Alexander's book offers tools for understanding and assessing the latest genetic discoveries critically.
To test the functional implications of impaired white matter (WM) connectivity among patients with schizophrenia and their relatives, we examined the heritability of fractional anisotropy (FA) measured on diffusion tensor imaging data acquired in Pittsburgh and Philadelphia, and its association with cognitive performance in a unique sample of 175 multigenerational non-psychotic relatives of 23 multiplex schizophrenia families and 240 unrelated controls (total = 438).
We examined polygenic inheritance (h2r) of FA in 24 WM tracts bilaterally, and also pleiotropy to test whether heritability of FA in multiple WM tracts is secondary to genetic correlation among tracts using the Sequential Oligogenic Linkage Analysis Routines. Partial correlation tests examined the correlation of FA with performance on eight cognitive domains on the Penn Computerized Neurocognitive Battery, controlling for age, sex, site and mother's education, followed by multiple comparison corrections.
Significant total additive genetic heritability of FA was observed in all three-categories of WM tracts (association, commissural and projection fibers), in total 33/48 tracts. There were significant genetic correlations in 40% of tracts. Diagnostic group main effects were observed only in tracts with significantly heritable FA. Correlation of FA with neurocognitive impairments was observed mainly in heritable tracts.
Our data show significant heritability of all three-types of tracts among relatives of schizophrenia. Significant heritability of FA of multiple tracts was not entirely due to genetic correlations among the tracts. Diagnostic group main effect and correlation with neurocognitive performance were mainly restricted to tracts with heritable FA suggesting shared genetic effects on these traits.
Many cognitive functions are under strong genetic control and twin studies have demonstrated genetic overlap between some aspects of cognition and schizophrenia. How the genetic relationship between specific cognitive functions and schizophrenia is influenced by IQ is currently unknown.
We applied selected tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB) to examine the heritability of specific cognitive functions and associations with schizophrenia liability. Verbal and performance IQ were estimated using The Wechsler Adult Intelligence Scale-III and the Danish Adult Reading Test. In total, 214 twins including monozygotic (MZ = 32) and dizygotic (DZ = 22) pairs concordant or discordant for a schizophrenia spectrum disorder, and healthy control pairs (MZ = 29, DZ = 20) were recruited through the Danish national registers. Additionally, eight twins from affected pairs participated without their sibling.
Significant heritability was observed for planning/spatial span (h2 = 25%), self-ordered spatial working memory (h2 = 64%), sustained attention (h2 = 56%), and movement time (h2 = 47%), whereas only unique environmental factors contributed to set-shifting, reflection impulsivity, and thinking time. Schizophrenia liability was associated with planning/spatial span (rph = −0.34), self-ordered spatial working memory (rph = −0.24), sustained attention (rph = −0.23), and set-shifting (rph = −0.21). The association with planning/spatial span was not driven by either performance or verbal IQ. The remaining associations were shared with performance, but not verbal IQ.
This study provides further evidence that some cognitive functions are heritable and associated with schizophrenia, suggesting a partially shared genetic etiology. These functions may constitute endophenotypes for the disorder and provide a basis to explore genes common to cognition and schizophrenia.
Which more importantly contributes to who we are and how we behave, biological influences or socio-cultural–environmental influences? This question reflects the essence of the “nature–nurture debate,” as traditionally defined. This debate and its appropriate resolution have important implications. At the same time, the nature–nurture debate is not profitably framed in this traditional way. The traditional framing implicitly assumes that “biological” and “environmental” causes – “nature” and “nurture” – constitute separable causes, as, say, pieces of a pie can be sliced apart and separated. In fact, they are not separable. To understand the effects of “nurture,” one must understand outcomes of “nature.” Within a reframing of the nature–nurture debate, one can ask a number of questions about the roles that nature and nurture play. We describe these questions. And we discuss some implications for understanding the sexes and, specifically, women.
Our current society is characterized by an increased availability of industrially processed foods with high salt, fat and sugar content. How is it that some people prefer these unhealthy foods while others prefer more healthy foods? It is suggested that both genetic and environmental factors play a role. The aim of this study was to (1) identify food preference clusters in the largest twin-family study into food preference to date and (2) determine the relative contribution of genetic and environmental factors to individual differences in food preference in the Netherlands. Principal component analysis was performed to identify the preference clusters by using data on food liking/disliking from 16,541 adult multiples and their family members. To estimate the heritability of food preference, the data of 7833 twins were used in structural equation models. We identified seven food preference clusters (Meat, Fish, Fruits, Vegetables, Savory snacks, Sweet snacks and Spices) and one cluster with Drinks. Broad-sense heritability (additive [A] + dominant [D] genetic factors) for these clusters varied between .36 and .60. Dominant genetic effects were found for the clusters Fruit, Fish (males only) and Spices. Quantitative sex differences were found for Meat, Fish and Savory snacks and Drinks. To conclude, our study convincingly showed that genetic factors play a significant role in food preference. A next important step is to identify these genes because genetic vulnerability for food preference is expected to be linked to actual food consumption and different diet-related disorders.
Over the last decade, extensive research effort has been placed on developing methane mitigation strategies in ruminants. Many disciplines on animal science disciplines have been involved, including nutrition and physiology, microbiology and genetic selection. To date, few of the suggested strategies have been implemented because: (1) methane emissions currently have no direct or indirect economic value for farmers, with no financial incentive to change practices and (2) most strategies have limited, or no, long-term effects. Consequently, there is a fundamental need for research on methane mitigation strategies across disciplines. Coordinated international initiatives similar to METHAGENE could represent highly relevant coordination tool of collaboration between countries, facilitating knowledge exchange, sharing concerns and building future collaborations.
Metabolites are small molecules involved in cellular metabolism where they act as reaction substrates or products. The term ‘metabolomics’ refers to the comprehensive study of these molecules. The concentrations of metabolites in biological tissues are under genetic control, but this is limited by environmental factors such as diet. In adult mono- and dizygotic twin pairs, we estimated the contribution of genetic and shared environmental influences on metabolite levels by structural equation modeling and tested whether the familial resemblance for metabolite levels is mainly explained by genetic or by environmental factors that are shared by family members. Metabolites were measured across three platforms: two based on proton nuclear magnetic resonance techniques and one employing mass spectrometry. These three platforms comprised 237 single metabolic traits of several chemical classes. For the three platforms, metabolites were assessed in 1407, 1037 and 1116 twin pairs, respectively. We carried out power calculations to establish what percentage of shared environmental variance could be detected given these sample sizes. Our study did not find evidence for a systematic contribution of shared environment, defined as the influence of growing up together in the same household, on metabolites assessed in adulthood. Significant heritability was observed for nearly all 237 metabolites; significant contribution of the shared environment was limited to 6 metabolites. The top quartile of the heritability distribution was populated by 5 of the 11 investigated chemical classes. In this quartile, metabolites of the class lipoprotein were significantly overrepresented, whereas metabolites of classes glycerophospholipids and glycerolipids were significantly underrepresented.