The genetic and environmental etiology of novel frequency-driven regional parcellations of abnormal white matter.

The prevalence of white matter disease increases with age and is associated with cerebrovascular disease, cognitive decline, and risk for dementia. MRI measures of abnormal signal in the white matter (AWM) provide estimates of damage, however, regional patterns of AWM may be differentially influenced by genetic or environmental factors. With our data-driven regional parcellation approach, we created a probability distribution atlas using Vietnam Era Twin Study of Aging (VETSA) data (n = 475, mean age 67.6 years) and applied a watershed algorithm to define separate regional parcellations. We report biometrical twin modeling for five anatomically distinct regions: (1) Posterior, (2) Superior frontal and parietal, (3) Anterior and inferior frontal with deep areas, (4) Occipital, and (5) Anterior periventricular. We tested competing multivariate hypotheses to identify unique influences and to explain sources of covariance among the parcellations. Family aggregation could be entirely explained by additive genetic influences, with additive genetic variance (heritability) ranging from 0.69 to 0.79. Most genetic correlations between parcellations ranged from moderate to high (rg = 0.57-0.85), although two were small (rg = 0.35-0.39), consistent with varying degrees of unique genetic influences. This proof-of-principle investigation demonstrated the value of our novel, data-driven parcellations, with identifiable genetic and environmental differences, for future exploration.

A comprehensive exploration of chronic kidney disease and dialysis in Canada's Indigenous population: from epidemiology to genetic influences.

PURPOSE: This study aims to review the escalating prevalence of chronic kidney disease (CKD) and end-stage renal disease (ESRD) among Canada's Indigenous population, focusing on risk factors, hospitalization and mortality rates, and disparities in kidney transplantation. The study explores how these factors contribute to the health outcomes of this population and examines the influence of genetic variations on CKD progression. METHODS: The review synthesizes data on prevalence rates, hospitalization and mortality statistics, and transplantation disparities among Indigenous individuals. It also delves into the complexities of healthcare access, including geographical, socioeconomic, and psychological barriers. Additionally, the manuscript investigates the impact of racial factors on blood characteristics relevant to dialysis treatment and the genetic predispositions influencing disease progression in Indigenous populations. RESULTS: Indigenous individuals exhibit a higher prevalence of CKD and ESRD risk factors such as diabetes and obesity, particularly in regions like Saskatchewan. These patients face a 77% higher risk of death compared to their non-Indigenous counterparts and are less likely to receive kidney transplants. Genetic analyses reveal significant associations between CKD and specific genomic variations. Through analyses, we found that healthy Indigenous individuals may have higher levels of circulating inflammatory markers, which could become further elevated for those with CKD. In particular, they may have higher levels of C-reactive protein (CRP) fibrinogen, as well as genomic variations that affect IL-6 production and the function of von Willebrand Factor (vWF) which has critical potential influence on the compatibility with dialysis membranes contributing to complications in dialysis. CONCLUSION: Indigenous people in Canada are disproportionately burdened by CKD and ESRD due to socioeconomic factors and potential genetic predispositions. While significant efforts have been made to assess the socioeconomic conditions of the Indigenous population, the genetic factors and their potential critical influence on compatibility with dialysis membranes, contributing to treatment complications, remain understudied. Further investigation into these genetic predispositions is essential.

Reciprocal Effects Between Negative Parenting and Children's Callous-Unemotional Traits From Mid to Late Childhood.

OBJECTIVE: The role of negative parenting in the development of callous-unemotional (CU) traits remains unclear. Both negative parenting and CU traits are influenced by genetic and environmental factors. The authors used genetically informed longitudinal cross-lagged models to examine the extent to which reciprocal effects between negative parenting and children's CU traits in mid-to-late childhood are genetic versus environmental in origin. METHODS: In 9,260 twin pairs from the Twins Early Development Study, the authors estimated cross-lagged effects between negative parenting (discipline and feelings) and children's CU traits in mid (ages 7-9) and late (ages 9-12) childhood. RESULTS: CU traits were strongly heritable and stable. Stability was explained largely by genetic factors. The influence of negative parenting on the development of CU traits was small and driven mostly by genetic and shared environmental factors. In mid childhood, the influence of children's CU traits on subsequent negative parenting (i.e., evoked by children's CU traits) was also small and mostly genetic in origin. In late childhood, CU traits showed no effects on negative parental discipline and small effects on negative parental feelings, which reflected mostly shared environmental factors. CONCLUSIONS: In mid-to-late childhood, genetic factors strongly influenced the development of CU traits, whereas environmental effects of negative parenting were small. Negative parenting was also relatively unaffected by CU traits. The small reciprocal effects originated mostly from genetic and shared environmental factors. Therefore, repeated intensive interventions addressing multiple risk factors rather than negative parenting alone may be best positioned to support families of children with CU traits across development.

Heritable Composite Phenotypes Defined by Combinations of Conduct Problem, Depression, and Temperament Features: Contributions to risk for Alcohol Problems.

The genetic architectures underlying symptoms of conduct problems and depression have largely been examined separately and without incorporating temperament, despite evidence for their genetic overlap. We examined how symptoms and temperament dimensions were transmitted together in families to identify highly heritable composite phenotypes, and how these composite phenotypes predicted alcohol outcomes in young adulthood. Participants (N = 486) were drawn from the third generation of families oversampled for alcohol use disorder in the first generation. Conduct problems, depression, and temperament were reported at 11-19 years old and alcohol outcomes at 18-26 years old. Using principal components of heritability analysis, we found seven highly heritable composite phenotypes, five of which predicted alcohol outcomes: three characterized by co-occurring conduct problems and depression and two by conduct problems. Novel composite phenotypes that were characterized by both conduct problems and depression showed different types of symptoms, temperament features, and genetic underpinnings. Children manifesting differing composite phenotypes might benefit from distinct treatments based on their unique etiologies.

A Comprehensive Review of Modifiable Cardiovascular Risk Factors and Genetic Influences in Dementia Prevention.

Dementia poses a growing global health challenge, demanding a multifaceted approach to prevention. This comprehensive review delves into the interplay between modifiable cardiovascular risk factors and genetic influences in dementia prevention. We examine key risk factors, including hypertension, diabetes, hyperlipidemia, obesity, smoking, and physical inactivity, elucidating their impact on dementia risk and the underlying biological mechanisms. Genetic factors, notably familial Alzheimer's disease (FAD) and the apolipoprotein E (APOE) gene, are explored in detail, offering insights into their contributions to dementia susceptibility. Importantly, we highlight the complex interrelationship between genetics and modifiable risk factors, emphasizing the need for personalized prevention strategies. Integrating lifestyle modifications and genetic considerations, a holistic approach is paramount in dementia prevention. Implications for public health initiatives and clinical practices underscore the urgency of tailored interventions. Our call to action urges continued research, precision medicine implementation, and collaborative efforts to mitigate the burden of dementia and enhance cognitive well-being globally.

Joint Consideration of Means and Variances Might Change the Understanding of Etiology.

Twin and adoption studies compare the similarities of people with differing degrees of relatedness to estimate genetic and environmental contributions to trait population variance. The analytic workhorse of these kinds of variance-focused designs is the intraclass correlation, which estimates similarity between pairs of individuals. Group means, by contrast, play no overt role in estimating genetic and environmental influences. Although this focus on variance has made very important contributions to understanding psychological characteristics, we contend that the exclusion of mean effects from behavioral genetic designs may have obscured key environmental influences and impeded full appreciation of the ubiquity and nature of gene-environment interplay in human outcomes. We provide empirical examples already in the literature and a theoretical framework for thinking through the incorporation of mean effects using largely forgotten, non-Mendelian theory regarding how genes influence human outcomes. We conclude that the field needs to develop models capable of fully incorporating mean effects into twin and adoption studies.

Family interactions in toddlerhood influence social competence in preschool age: Accounting for genetic and prenatal influences.

Identification of early promotive and risk factors for social competence is important for fostering children's successful social development; particularly given social competence is essential for children's later academic and psychological well-being. While research suggests that the early parent-child relationship, genetics, and prenatal influences are associated with social competence, there is less research considering how these factors may operate together to shape children's social competence in early childhood. Using a genetically informed sample from the Early Growth and Development Study (N = 561), we examined multiple levels of influence (i.e., genetic, prenatal, parenting, and child characteristics) on children's social competence at 4.5 years old. Results from structural equation models showed adoptive mother overreactivity at 18 months was positively associated with child dysregulation at 27 months, which, in turn, was associated with lower levels of social competence at 4.5 years. Also, child reactivity at 18 months was independently associated with higher levels of adoptive mother overreactivity at 27 months, which, in turn, was associated with lower levels of social competence at 4.5 years. Finally, we found an evocative effect on adoptive fathers' overreactivity at 18 months such that prenatal birth mother distress was negatively associated with adoptive fathers' overreactivity at 18 months. Overall, this study found evidence for genetic influences, and bidirectional associations between parent and child in toddlerhood that are related to lower levels of social competence when children were 4.5 years old. We also found that the prenatal environment was associated with parenting, but not with child behavior directly. This study's ability to simultaneously examine multiple domains of influence helps provide a more comprehensive picture of important mechanisms and developmental periods for children's early social competence.

Association between low back pain and body mass index in adult twins: an analysis of monozygotic and dizygotic twins of the Washington State Twin Registry.

BACKGROUND CONTEXT: Low back pain (LBP) is a common and significant cause of disability worldwide, however; questions about cause still remain. PURPOSE: To investigate the association between LBP, body mass index (BMI), and moderate to vigorous physical activity (MVPA) in a twin sample. STUDY DESIGN: Cross sectional study of monozygotic (MZ) and dizygotic (DZ) twins from the Washington State Twin Registry. PATIENT SAMPLE: Monozygotic and dizygotic twins from the Washington State Twin Registry. OUTCOME MEASURES: Self-report measures: Low back pain, body mass index, duration and intensity of exercise. METHODS: The sample included 5,183 same-sex pairs (69% MZ). The outcome was self-reported diagnosis of LBP from a health care provider. A phenotypic model tested the association between BMI and LBP without including genetic or shared environmental confounds. We then re-estimated the association using a quasi-causal model which controls for those confounds. Finally, we used a mediation model to investigate if the association between LBP and MVPA was mediated by BMI. RESULTS: In the phenotypic regression of LBP on BMI, there was a ~4-fold increase in the odds of having LBP with every one-unit increase in BMI (odds ratio [OR] =3.83; 95% confidence interval =3.28, 4.46). However, quasi-causal regression of LBP on BMI was reduced to zero (OR =0.95; 95% confidence interval =0.60, 1.49). A significant genetic background to BMI and LBP was present (bA =1.66; p<.001), even after controlling for confounders. In another analysis there was a significant direct effect between MVPA and LBP (bp=-0.092, standard error [SE] =0.017, p<.001). In mediation analysis, the effect of MVPA on LBP was partially mediated through MVPA effects on BMI ( [Formula: see text] =-0.043, SE=0.003, p<.001) and BMI effects on LBP ( [Formula: see text] =1.281, SE=0.079, OR=3.6, p<.001), however shared environmental factors confounded this relationship. CONCLUSIONS: BMI was not associated with LBP, despite sharing a phenotypic association, but they may share a genetic influence. The effect of MVPA on LBP is, in part, mediated by BMI but shared environment confounds this relationship. LEVEL OF EVIDENCE: Level 3.

The obesity epidemic - Nature via nurture: A narrative review of high-income countries.

Over the last three decades, the prevalence of obesity has increased rapidly in populations around the world. Despite a wealth of research, the relative contributions of the different mechanisms underlying this global epidemic are not fully understood. While there is growing consensus that the rapid rise in obesity prevalence has been driven by changes to the environment, it is evident that biology plays a central role in determining who develops obesity and who remains lean in the current obesogenic environment. This review summarises evidence on the extent to which genes and the environment influence energy intake and energy expenditure, and as a result, contribute to the ongoing global obesity epidemic. The concept of genetic susceptibility to the environment driving human variation in body weight is discussed.

Genetic and environmental influences on attention-deficit/hyperactivity disorder symptoms in Chinese adolescents: a longitudinal twin study.

Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder. However, no study has examined genetic and environmental influences in the longitudinal developmental course of ADHD symptoms in a non-Western population. This study investigated changes of genetic and environmental influences and their contributions to the stability and change of ADHD symptoms of hyperactivity/impulsivity and inattention in Chinese adolescent twins. A prospective sample of 602 twin pairs (48% male) self-reported both DSM-IV ADHD symptom subscales three times at the approximate age of 12, 13, and 15 years. Longitudinal multivariate genetic analyses through structural equation modelling examined genetic and environmental contributions to the developmental course of ADHD symptoms. From early (time 1 and 2) to middle adolescence (time 3), both symptoms showed modest and non-significant genetic influences that became substantial and significant, whereas shared environmental influences were substantial and significant and became modest and non-significant. The same genetic factors influenced ADHD symptoms throughout adolescence, while shared and non-shared environmental influences largely came from new emerging factors. In early adolescence, genetic factor contributed to the stability of inattention, whereas shared environmental factor contributed to the stability of hyperactivity/impulsivity. Genetic influences of ADHD tended to be smaller, whereas shared environmental influences tended to be larger in Chinese than in Western populations. Genetic factors played a large role in the stability of ADHD throughout adolescence, while shared and non-shared environment primarily contributed to its change. Findings highlight the importance of shared family, neighbourhood, and community experiences on child psychopathology in a collectivistic culture such as the Chinese society.

The Developmental Propensity Model Extends to Oppositional Defiant Disorder: a Twin Study.

Previous research has supported the developmental propensity model, which proposes that three socioemotional dispositions (prosociality, negative emotionality, and daring) increase risk for the development of conduct problems through shared genetic and environmental influences. The current study extends this research by examining the model in relation to oppositional defiant disorder (ODD). Based on a confirmatory factor analysis, ODD was examined as three separate dimensions (irritable, headstrong, and hurtful) rather than a unitary construct. Parents of 686 same-sex twins (ages 7-13) provided ratings of their twins' dispositions and ODD symptoms. Results from a path model examining phenotypic relationships showed that all dispositions were significantly related to each ODD dimension, except daring was not predictive of the irritable dimension. Preliminary twin analyses showed nonadditive genetic effects only on daring, which limited the appropriateness of evaluating it with the other dispositions. Results from a series of models used to examine etiological associations showed all ODD dimensions had common additive genetic influences with prosociality and negative emotionality. Only headstrong had common additive genetic influences with daring. Irritable and headstrong had common shared environmental influences with respect for rules (an aspect of prosociality), and common nonshared environmental influences with negative emotionality. Hurtful showed no shared environmental influences, but it had common nonshared environmental influences with prosociality and negative emotionality. These findings support the idea that the socioemotional dispositions in the developmental propensity model have some common etiological influences with ODD dimensions, suggesting this model can provide a novel framework for understanding the development of ODD.

Genetic and environmental influences on developmental trajectories of adolescent alcohol use.

Adolescent alcohol use demonstrates distinct developmental trajectories with different times of onset, levels, and rates of growth. Twin research on adolescent alcohol use has shown that genetic influences are consistent with a gradual growth of risks, whereas non-shared environmental influences are more consistent with an accumulation of risks over time. The current study investigated the relative contributions of genetic and environmental influences on shaping different developmental trajectories of alcohol use through adolescence. Self-reported past year alcohol use was collected from 877 Canadian twins (47.1% males) at age 13, 14, 15, and 17 years. Growth mixture models were fit to examine different developmental trajectories of alcohol use, and biometric liability threshold models were fit to investigate genetic and environmental influences on the liability of belonging to identified trajectories. Three trajectories were identified: low (15.1%), early onset (8.2%), and normative increasing (76.7%). Memberships in the low and early-onset group were under genetic (27.6% and 34.7%), shared (42.4% and 21.5%), and non-shared environment influences (30.0% and 43.8%). Membership in the normative increasing group was under genetic (37.7%) and non-shared environment influences (62.3%). Non-shared environmental influences were significantly larger for the normative increasing trajectory than for the low trajectory. These findings provide a more refined picture of genetic and environmental influences in the development of alcohol use in subgroups of adolescents. Genetic and environmental influences both matter, but to different degrees in different trajectories. Future research should identify specific shared and non-shared environmental experiences that distinguish different trajectories.

Genetics of serum carotenoid concentrations and their correlation with obesity-related traits in Mexican American children.

Background: Dietary intake of phytonutrients present in fruits and vegetables, such as carotenoids, is associated with a lower risk of obesity and related traits, but the impact of genetic variation on these associations is poorly understood, especially in children.Objective: We estimated common genetic influences on serum carotenoid concentrations and obesity-related traits in Mexican American (MA) children.Design: Obesity-related data were obtained from 670 nondiabetic MA children, aged 6-17 y. Serum α- and ß-carotenoid concentrations were measured in ∼570 (α-carotene in 565 and ß-carotene in 572) of these children with the use of an ultraperformance liquid chromatography-photodiode array. We determined heritabilities for both carotenoids and examined their genetic relation with 10 obesity-related traits [body mass index (BMI), waist circumference (WC), high-density lipoprotein (HDL) cholesterol, triglycerides, fat mass (FM), systolic and diastolic blood pressure, fasting insulin and glucose, and homeostasis model assessment of insulin resistance] by using family data and a variance components approach. For these analyses, carotenoid values were inverse normalized, and all traits were adjusted for significant covariate effects of age and sex.Results: Carotenoid concentrations were highly heritable and significant [α-carotene: heritability (h2) = 0.81, P = 6.7 × 10-11; ß-carotene: h2 = 0.90, P = 3.5 × 10-15]. After adjusting for multiple comparisons, we found significant (P ≤ 0.05) negative phenotypic correlations between carotenoid concentrations and the following traits: BMI, WC, FM, and triglycerides (range: α-carotene = -0.19 to -0.12; ß-carotene = -0.24 to -0.13) and positive correlations with HDL cholesterol (α-carotene = 0.17; ß-carotene = 0.24). However, when the phenotypic correlations were partitioned into genetic and environmental correlations, we found marginally significant (P = 0.051) genetic correlations only between ß-carotene and BMI (-0.27), WC (-0.30), and HDL cholesterol (0.31) after accounting for multiple comparisons. None of the environmental correlations were significant.Conclusions: The findings from this study suggest that the serum carotenoid concentrations were under strong additive genetic influences based on variance components analyses, and that the common genetic factors may influence ß-carotene and obesity and lipid traits in MA children.

Environmental Issues in Thyroid Diseases.

Environmental factors are determinant for the appearance of autoimmune thyroid diseases (AITD) in susceptible subjects. Increased iodine intake, selenium, and vitamin D deficiency, exposure to radiation, from nuclear fallout or due to medical radiation, are environmental factors increasing AITD. Cigarette smoking is associated with Graves' disease and Graves' ophthalmopathy, while it decreases the risk of hypothyroidism and thyroid autoimmunity. Viral infections are important environmental factors in the pathogenesis of AITD, too, particularly human parvovirus B19 (EVB19) and hepatitis C virus. Among the many chemical contaminants, halogenated organochlorines and pesticides variably disrupt thyroid function. Polychlorinated biphenyls and their metabolites and polybrominated diethyl ethers bind to thyroid transport proteins, such as transthyretin, displace thyroxine, and disrupt thyroid function. Among drugs, interferon- and iodine-containing drugs have been associated with AITD. Moreover intestinal dysbiosis causes autoimmune thyroiditis. To reduce the risk to populations and also in each patient, it is necessary to comprehend the association between environmental agents and thyroid dysfunction.

A National Swedish Longitudinal Twin-Sibling Study of alcohol use disorders among males.

AIMS: To examine whether genetic influences on the development of alcohol use disorders (AUD) among men during emerging adulthood through mid-adulthood are stable or dynamic. DESIGN: A twin study modeling developmental changes in the genetic and environmental influences on AUD during three age periods (18-25, 26-33 and 33-41) as a Cholesky decomposition. SETTING: Sweden. PARTICIPANTS: Swedish male twin pairs (1532 monozygotic and 1940 dizygotic) and 66 033 full male sibling pairs born less than 2 years apart. MEASUREMENTS: AUD was identified based on Swedish medical and legal registries. FINDINGS: The best-fitting model included additive genetic and unique environmental factors, with no evidence for shared environmental factors. Although the total heritability was stable over time, there were two major genetic factors contributing to AUD risk, one beginning at ages 18-25 with a modest decline in importance over time [0.84; confidence interval (CI) = 0.83-0.88], and another of less impact beginning at ages 26-33 with a modest increase in importance by ages 33-41 (0.31; CI = 0.05-0.47). CONCLUSIONS: The heritability of alcohol use disorders among Swedish men appears to be stable among three age periods: 18-25 years, 26-33 years, and 33-41 years. Two sets of genetic risk factors contribute to alcohol use disorders risk, with one originating during the ages 18-25 years and another coming online at 26-33 years, providing support for the developmentally dynamic hypothesis.

Factor structure and aetiological architecture of the BRIEF: A twin study.

Executive function is a broad construct that encompasses various processes involved in goal-directed behaviour in non-routine situations (Banich, 2009). The present study uses a sample of 560 5- to 16-year-old twin pairs (M = 11.14, SD = 2.53): 219 monozygotic twin pairs (114 female; 105 male) and 341 dizygotic twin pairs (136 female, 107 male; 98 opposite sex) to extend prior literature by providing information about the factor structure and the genetic and environmental architecture of the Behavior Rating Inventory of Executive Function (BRIEF; Gioia et al., 2000, Child Neuropsychol., 6, 235; Gioia et al., 2000, Behavior rating inventory of executive function, Lutz, FL: Psychological Assessment Resources), a multifaceted rating scale of everyday executive functions. Phenotypic results revealed a 9-scale, 3-factor model best represents the BRIEF structure within the current sample. Results of the genetically sensitive analyses indicated the presence of rater bias/contrast effects for the Initiate, Working Memory, and Task-Monitor scales. Additive genetic and non-shared environmental influences were present for the Initiate, Plan/Organize, Organization of Materials, Shift, and Monitor and Self-Monitor scales. Influences on Emotional Control were solely environmental. Interestingly, the aetiological architecture observed was similar to that of performance-based measures of executive function. This observed similarity provided additional evidence for the usefulness of the BRIEF as a measure of 'everyday' executive function.

The Rate of Change in Alcohol Misuse Across Adolescence is Heritable.

BACKGROUND: Alcohol use typically begins during adolescence and escalates into young adulthood. This represents an important period for the establishment of alcohol use and misuse patterns, which can have psychosocial and medical consequences. Although changes in alcohol use during this time have been phenotypically characterized, their genetic nature is poorly understood. METHODS: Participants of the Avon Longitudinal Study of Parents and Children completed the Alcohol Use Disorders Identification Test (AUDIT) 4 times from age 16 to 20. We used Mplus to construct a growth model characterizing changes in AUDIT scores across time (N = 4,545, where data were available for at least 2 time points). The slope of the model was used as the phenotype in a genomewide association study (N = 3,380), followed by secondary genetic analyses. RESULTS: No individual marker met genomewide significance criteria. Top markers mapped to biologically plausible candidate genes. The slope term was moderately heritable (h2SNP = 0.26, p = 0.009), and replication attempts using a meta-analysis of independent samples provided support for implicated variants at the aggregate level. Nominally significant (p < 0.00001) markers mapped to putatively active genomic regions in brain tissue more frequently than expected by chance. CONCLUSIONS: These results build on prior studies by demonstrating that common genetic variation impacts alcohol misuse trajectories. Influential loci map to genes that merit additional research, as well as to intergenic regions with regulatory functions in the central nervous system. These findings underscore the complex biological nature of alcohol misuse across development.