ADHD in Dutch adults: Heritability and linkage study

Attention deficit/hyperactivity disorder (ADHD) is a neurodevelopmental phenotype that persists into adulthood. This study investigated the heritability of inattentive and hyperactive symptoms and of total ADHD symptomatology load (ADHD index) in adults and performed linkage scans for these dimensions. Data on sibling pairs and their family members from the Netherlands Twin Register with genotype and phenotype data for inattention, hyperactivity and ADHD index (～750 sib‐pairs) were analyzed. Phenotypes were assessed with the short self‐report form of the Conners' Adult ADHD Rating Scales (CAARS). Heritabilities were estimated in SOLAR under polygenic models. Genome‐wide linkage scans were performed using variance components (VC) in MERLIN and MINX and model‐based linkage analysis was carried out in MENDEL with empirical evaluation of the results via simulations. Heritability estimates for inattention, hyperactivity and ADHD index were 35%, 23%, and 31%, respectively. Chromosomes 18q21.31–18q21.32 (VC LOD = 4.58, p_emp = 0.0026) and 2p25.1 (LOD = 3.58, p_emp = 0.0372) provided significant evidence for linkage for inattention and the ADHD index, respectively. The QTL on chromosome 2p25.1 also showed suggestive linkage for hyperactivity. Two additional suggestive QTLs for hyperactivity and the ADHD index shared the same location on chromosome 3p24.3–3p24.1. Finally, a suggestive QTL on 8p23.3–8p23.2 for hyperactivity was also found. Heritability of inattention, hyperactivity and total ADHD symptoms is lower in adults than in children. Chromosomes 18q and 2p are likely to harbor genes that influence several aspects of adult ADHD. © 2011 Wiley‐Liss, Inc.     

Linkage analyses of stimulant dependence,craving, and heavy use in American Indians

Amphetamine‐type substances are the second most widely used illicit drugs in the United States. There is evidence to suggest that stimulant use (cocaine and methamphetamine) has a heritable component, yet the areas of the genome underlying these use disorders are yet to be identified. This study's aims were to map loci linked to stimulant dependence, heavy use, and craving in an American Indian community at high risk for substance dependence. DSM diagnosis of stimulant dependence, as well as indices of stimulant “craving,” and “heavy use,” were obtained using the Semi‐Structured Assessment for the Genetics of Alcoholism (SSAGA). Genotypes were determined for a panel of 791 microsatellite polymorphisms in 381 members of multiplex families using SOLAR. Stimulant dependence, stimulant “craving,” and “heavy stimulant use,” were all found to be heritable. Analyses of multipoint variance component LOD scores, failed to yield evidence of linkage for stimulant dependence. For the stimulant “craving” phenotype, linkage analysis revealed a locus that had a LOD score of 3.02 on chromosome 15q25.3‐26.1 near the nicotinic receptor gene cluster. A LOD score of 2.05 was found at this same site for “heavy stimulant use.” Additional loci with LOD scores above 2.00 were found for stimulant “craving” on chromosomes 12p13.33‐13.32 and 18q22.3. These results corroborate the importance of “craving” as an important phenotype that is associated with regions on chromosome 12, 15, and 18, that have been highlighted in prior segregation studies in this and other populations for substance dependence‐related phenotypes. © 2011 Wiley‐Liss, Inc.     

Genetic Factor Analyses of Specific Cognitive Abilities in 5-Year-Old Dutch Children

The genetic and environmental factor structures of intellectual abilities in 5-year-old Dutch twins were examined. Six subtests of the RAKIT, a Dutch intelligence test, were administered to 209 twin pairs. The subtests were categorized as either verbal or nonverbal. The genetic covariance structure displayed a two-common factor structure including specific factors to account for subtest residual variance. The correlation between the genetic Verbal and genetic Nonverbal factors did not differ significantly from zero. The shared environmental influence displayed a single-common factor structure. Unique environmental influences did not contribute to the covariance between subtests and were specific in origin. Estimates of heritability of the subtests ranged from 15% to 56%. Shared environmental influences were significantly present, but were modest in magnitude. The phenotypic data was best described by an oblique two-factor model. This model was not mirrored in the factor structures found for either the genetic or environmental covariances.     

Breaking Through Artificial Selection Limits of an Adaptive Behavior in Mice and the Consequences for Correlated Responses

Previous divergent selection for nest-building behavior at 22 ± 1°C resulted in a 40-fold difference between the high and the low lines in amount of cotton used to build a nest. Correlated responses to selection indicated positive genetic correlations with body weight, nest-building at 4 ± 1°C, and litter size and negative genetic correlations with food consumption. At generation 46, the replicate high-selected (High 1 × High 2), randomly bred control (Control 1 × Control 2), and low-selected (Low 1 × Low 2) lines were crossed and the F₁ showed significant heterosis for nest-building behavior. Regression of the F₃ on the F₂ generation gave heritability estimates of 0.16 ± 0.10 for the high and 0.07 ± 0.10 for the low cross, revealing a potential to break the selection limit (at least in the high direction), which had been reached at about 20 generations of selection. Indeed, renewed selection resulted in responses in both the high and the low directions of nesting, yielding realized heritabilities of 0.29 ± 0.02 and 0.30 ± 0.004, respectively. Replicated renewed selection, using the F₃ generation as the base population, in the high direction of nesting resulted in correlated increases in nest-building at 4 ± 1°C, litter size, and food consumption. Body weight did not change. The positive correlation with food consumption is opposite in sign compared to the original selection experiment. This indicates that the evolutionary potential of a population to adapt to a changing environment not only depends on its current genetic variability in one adaptive trait, but may be constrained by genetic correlations changing over the course of selection.     

Heritability of serum dehydroepiandrosterone sulphate levels and pubertal development in 6∼18-year-old girls: a twin study

Background: Dehydroepiandrosterone sulphate (DHEAS), the most plentiful circulating adrenal hormone, may be considered as a marker of the onset of adrenarche and is involved in pubertal development and metabolic disorders.

Aim: The objective of this study is to determine the genetic and environmental influences on the variation of basal DHEAS levels and pubertal development in pubertal girls.

Subjects and methods: Three hundred and sixty twin girls aged 6–18-years were enrolled, consisting of 132 monozygotic pairs and 48 dizygotic pairs. Anthropometric and sexual characteristics were examined. Serum DHEAS was measured by RIA. Estimates of genetic and environmental components of variance were based on the theory of normal maximum likelihood in Mx package.

Results: Serum DHEAS concentrations of PH-II and PH-III were significantly higher than Tanner stage PH-I (p?heritability index of menarche, breast development and pube development are 0.71, 0.35 and 0.45, respectively.

Conclusions: Serum DHEAS concentrations of pubertal girls are mainly influenced by genetic factors, especially during the period of adrenarche. The results stress the importance of research into the genetic regulation of the endocrine regulators involved in adrenarche and related metabolic disorders in girls.     

Face processing among twins with and without autism: social correlates and twin concordance

Autism spectrum disorder (ASD) has a strong heritable basis, as evidenced by twin concordance rates. Within ASD, symptom domains may arise via independent genetic contributions, with varying heritabilities and genetic mechanisms. In this article, we explore social functioning in the form of (i) electrophysiological and behavioral measures of face processing (P1 and N170) and (ii) social behavior among child and adolescent twins with (N = 52) and without ASD (N = 66). Twins without ASD had better holistic face processing and face memory, faster P1 responses and greater sensitivity to the effects of facial inversion on P1. In contrast, N170 responses to faces were similar across diagnosis, with more negative amplitudes for faces vs non-face images. Across the sample, stronger social skills and fewer social difficulties were associated with faster P1 and N170 responses to upright faces, and better face memory. Twins were highly correlated within pairs across most measures, but correlations were significantly stronger for monozygotic vs dizygotic pairs on N170 latency and social problems. We suggest common developmental influences across twins for face processing and social behavior, but highlight (i) neural speed of face processing and (ii) social difficulties as important avenues in the search for genetic underpinnings in ASD.     

Heritability and genetic correlation between the cerebral cortex and associated white matter connections

The aim of this study is to investigate the genetic influence on the cerebral cortex, based on the analyses of heritability and genetic correlation between grey matter (GM) thickness, derived from structural MR images (sMRI), and associated white matter (WM) connections obtained from diffusion MRI (dMRI). We measured on sMRI the cortical thickness (CT) from a large twin imaging cohort using a surface‐based approach (N = 308, average age 22.8 ± 2.3 SD). An ACE model was employed to compute the heritability of CT. WM connections were estimated based on probabilistic tractography using fiber orientation distributions (FOD) from dMRI. We then fitted the ACE model to estimate the heritability of CT and FOD peak measures along WM fiber tracts. The WM fiber tracts where genetic influence was detected were mapped onto the cortical surface. Bivariate genetic modeling was performed to estimate the cross‐trait genetic correlation between the CT and the FOD‐based connectivity of the tracts associated with the cortical regions. We found some cortical regions displaying heritable and genetically correlated GM thickness and WM connectivity, forming networks under stronger genetic influence. Significant heritability and genetic correlations between the CT and WM connectivity were found in regions including the right postcentral gyrus, left posterior cingulate gyrus, right middle temporal gyri, suggesting common genetic factors influencing both GM and WM. Hum Brain Mapp 37:2331–2347, 2016. © 2016 Wiley Periodicals, Inc.     

Familial Aggregation and Heritability of Electrocardiographic Intervals and Heart Rate in a Rural Chinese Population

Background: Estimates of the genetic influences on electrocardiographic (ECG) parameters are inconsistent in previous reports, and no such studies have been performed in China. So we estimated genetic contributions to PR and QRS intervals and the rate‐adjusted QT interval (Bazett's QTc) in a Chinese rural population. Methods: A total of 2909 subjects from 847 families were enrolled in the current study. Genetic contributions to ECG parameters were estimated in two ways: correlation coefficients among family members (father‐mother, parent‐offspring, first sibling‐other sibling) and the heritability of each of the ECG parameters. Results: Our results showed significant correlations among family members on theses parameters: the correlation coefficients for PR interval, QRS duration, QTc interval, and HR, between parent‐sibling, and sibling‐sibling were 0.17 and 0.13, 0.18 and 0.23, 0.22 and 0.28, 0.19 and 0.18, respectively. The heritability for PR interval, QRS duration, QTc interval, and HR were estimated as 0.34, 0.43, 0.40, and 0.34, respectively. Conclusion: Genetic factors, together with the environmental and other cofactors contribute no more than 60% to the variance of the ECG intervals, supporting the concept that multiple factors, including gene‐gene and gene‐environment interactions could influence ECG interval phenotypes, and genetic factors play a major role.     

Familial aggregation of food allergy and sensitization to food allergens: a family-based study

Background The increasing prevalence of food allergy (FA) is a growing clinical and public health problem. The contribution of genetic factors to FA remains largely unknown. Objective This study examined the pattern of familial aggregation and the degree to which genetic factors contribute to FA and sensitization to food allergens. Methods This study included 581 nuclear families (2,004 subjects) as part of an ongoing FA study in Chicago, IL, USA. FA was defined by a set of criteria including timing, clinical symptoms obtained via standardized questionnaire interview and corroborative specific IgE cut‐offs for 95% positive predictive value (PPV) for food allergens measured by Phadia ImmunoCAP. Familial aggregation of FA as well as sensitization to food allergens was examined using generalized estimating equation (GEE) models, with adjustment for important covariates including age, gender, ethnicity and birth order. Heritability was estimated for food‐specific IgE measurements. Results FA in the index child was a significant and independent predictor of FA in other siblings (OR=2.6, 95% CI: 1.2–5.6, P=0.01). There were significant and positive associations among family members (father–offspring, mother–offspring, index–other siblings) for total IgE and specific IgE to all the nine major food allergens tested in this sample (sesame, peanut, wheat, milk, egg white, soy, walnut, shrimp and cod fish). The estimated heritability of food‐specific IgE ranged from 0.15 to 0.35 and was statistically significant for all the nine tested food allergens. Conclusion This family‐based study demonstrates strong familial aggregation of FA and sensitization to food allergens, especially, among siblings. The heritability estimates indicate that food‐specific IgE is likely influenced by both genetic and environmental factors. Together, this study provides strong evidence that both host genetic susceptibility and environmental factors determine the complex trait of IgE‐mediated FA.