Distinct Genetic Influences Research Articles

Multi-omics analysis of the molecular response to glucocorticoids - insights into shared genetic risk from psychiatric to medical disorders

BackgroundAlterations in the effects of glucocorticoids have been implicated in mediating some of the negative health effects associated with chronic stress, including increased risk for psychiatric disorders as well as cardiovascular and metabolic diseases. This study investigates how genetic variants influence gene expression and DNA methylation (DNAm) in response to glucocorticoid receptor (GR)-activation, and their association with disease risk. MethodsWe measured DNAm (n=199) and gene expression (n=297) in peripheral blood before and after GR-activation with dexamethasone, with matched genotype data available for all samples. A comprehensive molecular quantitative trait locus (QTL) analysis was conducted, mapping GR-response methylation (me)QTLs, GR-response expression (e)QTLs, and GR-response expression quantitative trait methylation (eQTM). A multi-level network analysis was employed to map the complex relationships between the transcriptome, epigenome, and genetic variation. ResultsWe identified 3,772 GR-response meCpGs corresponding to 104,828 local GR-response meQTLs that did not strongly overlap with baseline meQTLs. eQTM and eQTL analyses revealed distinct genetic influences on gene expression and DNAm. Multi-level network analysis uncovered GR-response network trio QTLs, characterized by SNP-CpG-transcript combinations where meQTLs act as both eQTLs and eQTMs. GR-response trio variants were enriched in GWAS for psychiatric, respiratory, autoimmune and cardiovascular diseases and conferred a higher relative heritability per SNP than GR-response meQTL and baseline QTL SNP. ConclusionsGenetic variants modulating the molecular effects of glucocorticoids are associated with psychiatric as well as medical diseases and not uncovered in baseline QTL analyses.

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth.

Evidence for distinct genetic and environmental influences on fear acquisition and extinction.

Anxiety disorders are highly prevalent with an early age of onset. Understanding the aetiology of disorder emergence and recovery is important for establishing preventative measures and optimising treatment. Experimental approaches can serve as a useful model for disorder and recovery relevant processes. One such model is fear conditioning. We conducted a remote fear conditioning paradigm in monozygotic and dizygotic twins to determine the degree and extent of overlap between genetic and environmental influences on fear acquisition and extinction. In total, 1937 twins aged 22-25 years, including 538 complete pairs from the Twins Early Development Study took part in a fear conditioning experiment delivered remotely via the Fear Learning and Anxiety Response (FLARe) smartphone app. In the fear acquisition phase, participants were exposed to two neutral shape stimuli, one of which was repeatedly paired with a loud aversive noise, while the other was never paired with anything aversive. In the extinction phase, the shapes were repeatedly presented again, this time without the aversive noise. Outcomes were participant ratings of how much they expected the aversive noise to occur when they saw either shape, throughout each phase. Twin analyses indicated a significant contribution of genetic effects to the initial acquisition and consolidation of fear, and the extinction of fear (15, 30 and 15%, respectively) with the remainder of variance due to the non-shared environment. Multivariate analyses revealed that the development of fear and fear extinction show moderate genetic overlap (genetic correlations 0.4-0.5). Fear acquisition and extinction are heritable, and share some, but not all of the same genetic influences.

Polygenic scores for smoking and educational attainment have independent influences on academic success and adjustment in adolescence and educational attainment in adulthood.

Educational success is associated with greater quality of life and depends, in part, on heritable cognitive and non-cognitive traits. We used polygenic scores (PGS) for smoking and educational attainment to examine different genetic influences on facets of academic adjustment in adolescence and educational attainment in adulthood. PGSs were calculated for participants of the Minnesota Twin Family Study (N = 3225) and included as predictors of grades, academic motivation, and discipline problems at ages 11, 14, and 17 years-old, cigarettes per day from ages 14 to 24 years old, and educational attainment in adulthood (mean age 29.4 years). Smoking and educational attainment PGSs had significant incremental associations with each academic variable and cigarettes per day. About half of the adjusted effects of the smoking and education PGSs on educational attainment in adulthood were mediated by the academic variables in adolescence. Cigarettes per day from ages 14 to 24 years old did not account for the effect of the smoking PGS on educational attainment, suggesting the smoking PGS indexes genetic influences related to general behavioral disinhibition. In sum, distinct genetic influences measured by the smoking and educational attainment PGSs contribute to academic adjustment in adolescence and educational attainment in adulthood.

Shared and Distinct Genetic Influences Between Cognitive Domains and Psychiatric Disorder Risk Based on Genome-Wide Data

Group-level cognitive performance differences are found in psychiatric disorders ranging from depression to autism to schizophrenia. Understanding the genetic underpinnings of specific cognitive abilities, and their relationships to psychiatric disorder risk, can inform the understanding of disease biology nosology and etiology.

Genetic Analysis of Stem Diameter and Water Contents To Improve Sorghum Bioenergy Efficiency.

Biofuel made from agricultural products has the potential in contribute to a stable supply of fuel for growing energy demands. Some salient plant traits, such as stem diameter and water content, and their relationship to other important biomass-related traits are so far poorly understood. Here, we performed QTL mapping for three stem diameter and two water content traits in a S. bicolor BTx623 x IS3620c recombinant inbred line population of 399 genotypes, and validated the genomic regions identified using genome-wide association studies (GWAS) in a diversity panel of 354 accessions. The discovery of both co-localized and non-overlapping loci affecting stem diameter traits suggests that stem widths at different heights share some common genetic control, but also have some distinct genetic influences. Co-localizations of stem diameter and water content traits with other biomass traits including plant height, flowering time and the ‘dry’ trait, suggest that their inheritance may be linked functionally (pleiotropy) or physically (linkage disequilibrium). Water content QTL in homeologous regions resulting from an ancient duplication event may have been retained and continue to have related functions for an estimated 96 million years. Integration of QTL and GWAS data advanced knowledge of the genetic basis of stem diameter and water content components in sorghum, which may lead to tools and strategies for either enhancing or suppressing these traits, supporting advances toward improved quality of plant-based biomass for biofuel production.

Generalized, focal, and combined epilepsies in families: New evidence for distinct genetic factors.

To determine the roles of shared and distinct genetic influences on generalized and focal epilepsy operating in individuals who manifest features of both types (combined epilepsies), and in families manifesting both generalized and focal epilepsies in separate individuals (mixed families). We analyzed the deeply phenotyped Epi4K cohort of multiplex families (≥3 affected individuals per family) using methods that quantify the aggregation of phenotypes within families and the relatedness of individuals with different phenotypes within family pedigrees. The cohort included 281 families containing 1021 individuals with generalized (n=484), focal (304), combined (51), or unclassified (182) epilepsies. The odds of combined epilepsy was higher in relatives of participants with combined epilepsy than in relatives of those with other epilepsy types (odds ratio [OR] 5.2, 95% confidence interval [CI] 1.7-16.1, P=.004). Individuals with combined epilepsy co-occurred in families more often than expected by chance (P=.03). Within mixed families, individuals with each type of epilepsy were more closely related to relatives with the same type than to relatives with other types (P<.001). These findings suggest that distinct genetic influences underlie the recently recognized entity of combined epilepsies, just as generalized epilepsies and focal epilepsies each have distinct genetic influences. Mixed families may in part reflect chance co-occurrence of these distinct genetic influences. These conclusions have important implications for molecular genetic studies aimed at identifying genetic determinants of the epilepsies.

OLIG2 gene polymorphisms are associated with nasty, unpleasant and uncontrollable thoughts in obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is one of 10 major debilitating neuropsychiatric disorders, according to the World Health Organization (WHO), affecting around 2.3% of people worldwide. Obsessive-compulsive symptoms are caused by shared or distinct genetic or environmental influences. Several imaging studies have detected white-matter alterations in OCD, and recent studies have demonstrated thatOCD is associated with variations in the OLIG2 gene. The aim of this study was to investigate whether OLIG2 gene is associated with OCD and its clinical features in a Brazilian sample. We genotyped three variants in OLIG2 gene, rs762178, rs1059004, and rs9653711 in 205 OCD patients and 202 healthy controls by Taqman® methodology. Genotypes and alleles distributions were analyzed by χ2 or Fisher exact tests. The rs762178 and rs9653711 polymorphisms were significantly associated with OCD (P = 0.048 and 0.029, respectively). We also observed an association of rs1059004 and rs9653711 with the presence of Obsessive-Compulsive Inventory-Revised (OCI-R) obsessing (unacceptable thoughts) subscore (P = 0.031 and 0.034, respectively). Moreover, the pair of loci consisting of rs762178 and rs9653711 A-G haplotype was associated with OCD (P < 0.0001). The OLIG2 gene may be involved in OCD, particularly in patients showing nasty, unpleasant and uncontrollable thoughts. However, more studies in larger samples are needed to replicate these findings.

Understanding Comorbidity Between Specific Learning Disabilities.

Current definitions of specific learning disability (SLD) identify a heterogeneous population that includes individuals with weaknesses in reading, math, or writing, and these academic difficulties often co-occur in many of the same individuals. The Colorado Learning Disabilities Research Center (CLDRC) is an interdisciplinary, multisite research program that uses converging levels of analysis to understand the genetic and environmental etiology, neuropsychology, and developmental outcomes of SLDs in reading (RD), math (MD), and writing (WD), along with the comorbidity between these SLDs and other developmental disorders. The latest results from the CLDRC twin study suggest that shared genetic influences contribute to the significant covariance between all aspects of reading (word reading, reading fluency, and reading comprehension) and math (calculations, math fluency, and word problems), and distinct genetic or environmental influences also contribute to weaknesses in each specific academic domain. RD and MD are associated with a range of negative outcomes on both concurrent measures and measures of functional outcomes completed 5 years after the twins were first assessed. Over the next several years the CLDRC will continue to expand on this work by administering a comprehensive test battery that includes measures of all dimensions of academic achievement that are described in current definitions of SLD and incorporating these measures in new neuroimaging and molecular genetic studies.

SA5 - GAENETICS OF WORKING MEMORY AND VIGILANCE EDOPHENOTYPES IN ADHD

Background Joint genetic analysis of correlated endophenotypes markedly enhances insight into the relationships among them and the shared and distinct genetic influences on phenotypically related complex traits. In addition, identifying pleiotropic effects among endophenotypes can help improve our biological understanding of the genetic architecture of a complex disease, namely childhood Attention Deficit Hyperactivity Disorder (ADHD). Cognitive functions, in particular aspects of executive functioning, have long been proposed as endophenotypes for ADHD, in some cases with distinct components of ADHD emphasized (hyperactivity and inattention-disorganization). This study identifies and characterizes the individual and shared genetic variants associated with two major cognitive endophenotypes—Working Memory (WM) and arousal — in relation to both ADHD sub-dimensions. Methods Composite scores for working memory and arousal were created on the basis of a latent variable model using multiple laboratory-obtained measures of each construct. Inattention and hyperactivity were defined on the basis of a composite of parental and teacher ratings. A confirmatory factor model fit well, supporting the internal validity of the composite scores. Subjects included 656 unrelated community recruited volunteer children ranging 7 to 13 years old (n=435 ADHD, 221 non-ADHD). SNPs included in our analysis (n=193,657) were from a polygenic risk score (PGS) computed using the reported discovery sample of 20,183 ADHD cases and 35,191 controls from the Psychiatric Genetics Consortium. A linear regression analysis accounting for age, sex and population stratification was used to test for association to each endophenotype. Pleiotropic relationships were identified using linear regression analysis accounting for the correlation among all four phenotype measures. A likelihood ratio test framework was used for inferring the number of traits associated with a genetic variant and for partitioning traits associated with the different SNPs. Results The PGS was associated with ADHD diagnosis (Nagelkerke R2=.04, p=0.0000006) and multi-indicator dimensional ADHD latent variables by parent report (beta=.196, SE=.041) and teacher report (beta=.176, SE=.040). Univariate SNP associations (p Discussion Our study provides motivation for pleiotropic effects in ADHD endophenotypes and helps begin to account for the mechanism by which cognitive endophenotypes participate in ADHD development.

Evidence for a genetic effect in altered cortical surface area but not in cortical thinning in siblings of patients with mesial temporal lobe epilepsy: Commentary on: "Abnormal temporal lobe morphology in asymptomatic relatives of patients with hippocampal sclerosis: A replication study".

Although studies have shown cortical and subcortical changes in first-degree relatives of patients with familial forms of temporal lobe epilepsy, few studies have addressed extrahippocampal morphology changes in unaffected siblings of patients with sporadic mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS). Alhusaini et al1 described subtle reduced cortical volumes in the anteromedial temporal cortex of asymptomatic siblings of sporadic MTLE-HS patients, suggesting that such localized traits are possibly heritable. In this issue of Epilepsia, Yaakub et al2 replicated these findings in first-degree asymptomatic relatives of patients with MTLE-HS.2 A positive history of simple febrile convulsions before the age of 4 years was present in two relatives in this study.2 Both these relatives had values above the median of the relative group for the reduced surface area in the anteromedial temporal cortex, further strengthening the possibility that these subtle morphological changes are inherited.2 Limitations of this study include the small number of subjects studied and that they side-flipped the images to increase power to detect differences, thus treating both hemispheres as if they were equal, which is not the case, as shown recently by Kong et al.3 The study by Alhusaini et al1 showed that the alterations of cortical morphology found in anteromedial regions of unaffected siblings of subjects with left MTLE-HS (more in the left entorhinal cortex and parahippocampal gyrus) differed from those found in unaffected siblings of subjects with right MTLE-HS (more in the right entorhinal cortex and temporal pole). It is of relevance that both studies1, 2 used FreeSurfer (http://surfer.nmr.mgh.harvard.edu), which measures cortical volume as a product of two distinct aspects of the cortical architecture: cortical thickness and surface area.4 Cortical thickness and surface area measurements appear to represent different early neurodevelopmental events with distinct genetic influences, as shown by Panizzon et al5 in a magnetic resonance imaging study of twins. They found that, although cortical thickness and surface area are both highly heritable (>0.80), they are mostly unrelated genetically (genetic correlation = 0.08).5 These results suggest some independence of these two surface-based measures, and potentially, their asymmetry patterns. A recent study that mapped cortical brain asymmetry in 17 141 healthy individuals showed regions with different asymmetrical patterns in cortical thickness and surface area and a significant heritability of these asymmetry characteristics.3 Effect sizes of cortical thickness and surface area were independent, and the asymmetry was generally more prominent for surface area compared with that of cortical thickness.3 Most regions showed significant asymmetry in surface area, although with no clear directional pattern affecting neighboring regions, or along the anterior-posterior axis, as they observed for cortical thickness.3 Widespread cerebral cortical thinning has been identified in patients with MTLE as compared to healthy controls within several cortical regions, including the mesiotemporal, limbic, and central sensorimotor cortices.6 This pattern of cortical thinning appeared progressive in patients with medically refractory epilepsy,6 but also to a lesser degree in MTLE patients under seizure control.7 Less attention has been paid to cortical surface area in studies of MTLE patients. Interestingly, both Alhusaini et al1 and Yaakub et al2 found reduced cortical surface areas in anteromedial temporal regions of asymptomatic siblings of sporadic MTLE-HS patients, but no significant changes in cortical thickness. This lack of cortical thickness changes has been confirmed in 127 asymptomatic first-degree relatives of MTLE-HS patients from three independent cohorts, each with a healthy control group.8 These findings altogether indicate that the previously characterized progressive cortical thinning in patients with MTLE-HS is not heritable and is likely driven by disease-related factors, whereas changes in the cortical surface area may represent an inherited trait that preceded seizure onset. This hypothesis needs to be confirmed in further studies with multiple large cohorts, also taking into account the asymmetric nature of cerebral hemispheres. The author has no conflict of interest to disclose. I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Distinct Genetic Influences on Cortical and Subcortical Brain Structures.

This study examined the heritability of brain grey matter structures in a subsample of older adult twins (93 MZ and 68 DZ twin pairs; mean age 70 years) from the Older Australian Twins Study. The heritability estimates of subcortical regions ranged from 0.41 (amygdala) to 0.73 (hippocampus), and of cortical regions, from 0.55 (parietal lobe) to 0.78 (frontal lobe). Corresponding structures in the two hemispheres were influenced by the same genetic factors and high genetic correlations were observed between the two hemispheric regions. There were three genetically correlated clusters, comprising (i) the cortical lobes (frontal, temporal, parietal and occipital lobes); (ii) the basal ganglia (caudate, putamen and pallidum) with weak genetic correlations with cortical lobes, and (iii) the amygdala, hippocampus, thalamus and nucleus accumbens grouped together, which genetically correlated with both basal ganglia and cortical lobes, albeit relatively weakly. Our study demonstrates a complex but patterned and clustered genetic architecture of the human brain, with divergent genetic determinants of cortical and subcortical structures, in particular the basal ganglia.

Schizophrenia genetics complements its mechanistic understanding.

Refinement of genetic variants within the major histocompatibility complex reveals three distinct genetic influences on schizophrenia risk and sheds light on the disease's neurobiology.

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.

White matter disease in midlife is heritable, related to hypertension, and shares some genetic influence with systolic blood pressure.

White matter disease in the brain increases with age and cardiovascular disease, emerging in midlife, and these associations may be influenced by both genetic and environmental factors. We examined the frequency, distribution, and heritability of abnormal white matter and its association with hypertension in 395 middle-aged male twins (61.9 ± 2.6 years) from the Vietnam Era Twin Study of Aging, 67% of whom were hypertensive. A multi-channel segmentation approach estimated abnormal regions within the white matter. Using multivariable regression models, we characterized the frequency distribution of abnormal white matter in midlife and investigated associations with hypertension and Apolipoprotein E-ε4 status and the impact of duration and control of hypertension. Then, using the classical twin design, we estimated abnormal white matter heritability and the extent of shared genetic overlap with blood pressure. Abnormal white matter was predominantly located in periventricular and deep parietal and frontal regions; associated with age (t = 1.9, p = 0.05) and hypertension (t = 2.9, p = 0.004), but not Apolipoprotein ε4 status; and was greater in those with uncontrolled hypertension relative to controlled (t = 3.0, p = 0.003) and normotensive (t = 4.0, p = 0.0001) groups, suggesting that abnormal white matter may reflect currently active cerebrovascular effects. Abnormal white matter was highly heritable (a2 = 0.81) and shared some genetic influences with systolic blood pressure (rA = 0.26), although there was evidence for distinct genetic contributions and unique environmental influences. Future longitudinal research will shed light on factors impacting white matter disease presentation, progression, and potential recovery.

Two Patterns of White Matter Abnormalities in Medication-Naive Patients With First-Episode Schizophrenia Revealed by Diffusion Tensor Imaging and Cluster Analysis.

Accumulating evidence supports the hypothesis that cerebral white matter abnormalities are involved in the pathophysiology of schizophrenia; however, findings from in vivo neuroimaging studies have been inconsistent. Besides confounding factors, including age, illness duration, and medication effects, an additional cause for the inconsistent results may be heterogeneity in the nature of white matter alterations associated with the disorder. To investigate whether different patterns of white matter abnormalities exist in a large cohort of medication-naive patients with first-episode schizophrenia and the relationship between such patterns and clinical parameters. A cross-sectional diffusion tensor imaging study of 113 medication-naive patients with first-episode schizophrenia and 110 demographically matched healthy control individuals. The study was conducted in the mental health center of West China Hospital, Sichuan University, Chengdu, China, from January 2006 to June 2014. The patterns of white matter abnormalities revealed by tract-specific analysis in conjunction with hierarchical clustering. With diffusion features extracted from 18 fiber tracts, cluster analysis revealed 2 patterns of abnormalities. One pattern (42.5% of patient sample) showed widespread white matter abnormalities compared with matched healthy control individuals, while another pattern (57.5% of patient sample) only showed circumscribed regional white matter abnormalities, mainly in the left superior longitudinal fasciculus. Patients in these subgroups did not differ in demographic features; however, negative symptoms were more severe in patients with widespread white matter abnormalities. Two distinct patterns of white matter abnormalities exist at the early phase of schizophrenia, with those having global abnormalities experiencing more severe negative symptoms. The finding that distinct subgroups of patients with schizophrenia have different forms of white matter pathology may reflect qualitatively distinct genetic influences or neurodevelopmental alterations and thus represents a promising strategy for resolving neurobiological heterogeneity in the schizophrenia syndrome.

The glass is half full and half empty: A population-representative twin study testing if optimism and pessimism are distinct systems

Optimism and pessimism are associated with important outcomes including health and depression. Yet it is unclear if these apparent polar opposites form a single dimension or reflect two distinct systems. The extent to which personality accounts for differences in optimism/pessimism is also controversial. Here, we addressed these questions in a genetically informative sample of 852 pairs of twins. Distinct genetic influences on optimism and pessimism were found. Significant family-level environment effects also emerged, accounting for much of the negative relationship between optimism and pessimism, as well as a link to neuroticism. A general positive genetics factor exerted significant links among both personality and life-orientation traits. Both optimism bias and pessimism also showed genetic variance distinct from all effects of personality and from each other.

Polymorphisms in TICAM2 and IL1B are associated with TB.

BackgroundHuman genetic susceptibility for tuberculosis (TB) has been demonstrated by several studies, but few have examined multiple innate and adaptive immunity genes comprehensively, age-specific effects, and/or resistance to Mycobacterium tuberculosis (Mtb) infection (RSTR). We hypothesized that RSTR, defined by a persistently negative tuberculin skin test, may have different genetic influences than Mtb disease.MethodsWe examined 29 candidate genes in pathways that mediate immune responses to Mtb in subjects in a household contact study in Kampala, Uganda. We genotyped 546 haplotype-tagging single nucleotide polymorphisms (SNPs) in 835 individuals from 481 families; 28.7% had TB, 10.5% were RSTR, and the remaining 60.8% had latent Mtb infection.ResultsAmong our most significant findings were SNPs in TICAM2 (p=3.6×10−6) and IL1B (p=4.3×10−5) associated with TB. Multiple SNPs in IL4 and TOLLIP were associated with TB (p<0.05). Age-genotype interaction analysis revealed SNPs in IL18 and TLR6 that were suggestively associated with TB in children ≤ 10 years old (p=2.9×10−3). By contrast, RSTR was associated with SNPs in NOD2, SLC6A3 and TLR4 (nominal p < 0.05); these genes were not associated with TB, suggesting distinct genetic influences.ConclusionsWe report the first association between TICAM2 polymorphisms and TB, and between IL18 and pediatric TB.

Corpus callosum size is highly heritable in humans, and may reflect distinct genetic influences on ventral and rostral regions.

Anatomical differences in the corpus callosum have been found in various psychiatric disorders, but data on the genetic contributions to these differences have been limited. The current study used morphometric MRI data to assess the heritability of corpus callosum size and the genetic correlations among anatomical sub-regions of the corpus callosum among individuals with and without mood disorders. The corpus callosum (CC) was manually segmented at the mid-sagittal plane in 42 women (healthy, n = 14; major depressive disorder, n = 15; bipolar disorder, n = 13) and their 86 child or adolescent offspring. Four anatomical sub-regions (CC-genu, CC2, CC3 and CC-splenium) and total CC were measured and analyzed. Heritability and genetic correlations were estimated using a variance components method, with adjustment for age, sex, diagnosis, and diagnosis x age, where appropriate. Significant heritability was found for several CC sub-regions (P<0.01), with estimated values ranging from 48% (splenium) to 67% (total CC). There were strong and significant genetic correlations among most sub regions. Correlations between the genu and mid-body, between the genu and total corpus callosum, and between anterior and mid body were all >90%, but no significant genetic correlations were detected between ventral and rostral regions in this sample. Genetic factors play an important role in corpus callosum size among individuals. Distinct genetic factors seem to be involved in caudal and rostral regions, consistent with the divergent functional specialization of these brain areas.

Prevalence and heritability of obsessive-compulsive spectrum and anxiety disorder symptoms: A survey of the Australian Twin Registry.

While past twin studies indicate moderate levels of heritability of "obsessive-compulsive related" and anxiety disorder symptoms, no single study has reported such estimates in the same twin population nor examined potential genetic sex differences. We assessed symptoms of obsessive-compulsive disorder, body dysmorphic disorder, hoarding disorder, hypochondriasis, panic disorder, social phobia and generalized anxiety disorder in 2,495 adult twins (1,468 female). Prevalence estimates for the corresponding symptom measures were determined using empirically derived cut-off scores. Twin resemblance was assessed by Pearson correlations and biometrical model-fitting analyses, incorporating sex-specific effects, using OpenMx. Prevalence estimates ranged from 1.6% in the symptoms of generalized anxiety to 16.9% for social phobia. Female twins demonstrated significantly higher prevalence rates across all domains with the exception of obsessive-compulsive symptoms. Additive genetic factors accounted for a moderate proportion of the total liability to each symptom domain. Evidence suggesting qualitative genetic sex differences (i.e., distinct genetic influences between genders) was observed for body dysmorphic concern and panic symptoms, while quantitative differences were observed for hoarding and social phobia symptoms, indicating stronger heritability in females. Novel findings in this study include the observation of probable genetic sex differences in liability towards hoarding symptoms and dysmorphic concern, as well as the lack of such differences in hypochondriasis. The trend towards qualitative sex differences in panic symptoms has some intuitive appeal with regard to biological-experimental models of panic.