Multilevel Twin Models: Geographical Region as a Third Level Variable.

The classical twin model can be reparametrized as an equivalent multilevel model. The multilevel parameterization has underexplored advantages, such as the possibility to include higher-level clustering variables in which lower levels are nested. When this higher-level clustering is not modeled, its variance is captured by the common environmental variance component. In this paper we illustrate the application of a 3-level multilevel model to twin data by analyzing the regional clustering of 7-year-old children's height in the Netherlands. Our findings show that 1.8%, of the phenotypic variance in children's height is attributable to regional clustering, which is 7% of the variance explained by between-family or common environmental components. Since regional clustering may represent ancestry, we also investigate the effect of region after correcting for genetic principal components, in a subsample of participants with genome-wide SNP data. After correction, region no longer explained variation in height. Our results suggest that the phenotypic variance explained by region might represent ancestry effects on height.

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence.

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

Do DSM-5 Section II personality disorders and Section III personality trait domains reflect the same genetic and environmental risk factors?

BACKGROUND: DSM-5 includes two conceptualizations of personality disorders (PDs). The classification in Section II is identical to the one found in DSM-IV, and includes 10 categorical PDs. The Alternative Model (Section III) includes criteria for dimensional measures of maladaptive personality traits organized into five domains. The degree to which the two conceptualizations reflect the same etiological factors is not known. METHODS: We use data from a large population-based sample of adult twins from the Norwegian Institute of Public Health Twin Panel on interview-based DSM-IV PDs and a short self-report inventory that indexes the five domains of the DSM-5 Alternative Model plus a domain explicitly targeting compulsivity. Schizotypal, Paranoid, Antisocial, Borderline, Avoidant, and Obsessive-compulsive PDs were assessed at the same time as the maladaptive personality traits and 10 years previously. Schizoid, Histrionic, Narcissistic, and Dependent PDs were only assessed at the first interview. Biometric models were used to estimate overlap in genetic and environmental risk factors. RESULTS: When measured concurrently, there was 100% genetic overlap between the maladaptive trait domains and Paranoid, Schizotypal, Antisocial, Borderline, and Avoidant PDs. For OCPD, 43% of the genetic variance was shared with the domains. Genetic correlations between the individual domains and PDs ranged from +0.21 to +0.91. CONCLUSION: The pathological personality trait domains, which are part of the Alternative Model for classification of PDs in DSM-5 Section III, appears to tap, at an aggregate level, the same genetic risk factors as the DSM-5 Section II classification for most of the PDs.

Testing Causal Effects of Maternal Smoking During Pregnancy on Offspring's Externalizing and Internalizing Behavior.

Maternal smoking during pregnancy (SDP) is associated with increased risk of externalizing and internalizing behaviors in offspring. Two explanations (not mutually exclusive) for this association are direct causal effects of maternal SDP and the effects of genetic and environmental factors common to parents and offspring which increase smoking as well as problem behaviors. Here, we examined the associations between parental SDP and mother rated offspring externalizing and internalizing behaviors (rated by the Child Behavior Checklist/2-3) at age three in a population-based sample of Dutch twins (N = 15,228 pairs). First, as a greater effect of maternal than of paternal SDP is consistent with a causal effect of maternal SDP, we compared the effects of maternal and paternal SDP. Second, as a beneficial effect of quitting smoking before pregnancy is consistent with the causal effect, we compared the effects of SDP in mothers who quit smoking before pregnancy, and mothers who continued to smoke during pregnancy. All mothers were established smokers before their pregnancy. The results indicated a greater effect of maternal SDP, compared to paternal SDP, for externalizing, aggression, overactive and withdrawn behavior. Quitting smoking was associated with less externalizing, overactive behavior, aggression, and oppositional behavior, but had no effect on internalizing, anxious depression, or withdrawn behavior. We conclude that these results are consistent with a causal, but small, effect of smoking on externalizing problems at age 3. The results do not support a causal effect of maternal SDP on internalizing behaviors.

The heritability of alcohol use disorders: a meta-analysis of twin and adoption studies.

BACKGROUND: To clarify the role of genetic and environmental risk factors in alcohol use disorders (AUDs), we performed a meta-analysis of twin and adoption studies and explored the impact of sex, assessment method (interview v. hospital/population records), and study design (twin v. adoption study) on heritability estimates. METHOD: The literature was searched for all unique twin and adoption studies of AUD and identified 12 twin and five adoption studies. The data were then reconstructed and analyzed using ordinal data full information maximum likelihood in the OpenMx program. Heterogeneity was tested with likelihood ratio tests by equating the parameters across studies. RESULTS: There was no evidence for heterogeneity by study design, sex or assessment method. The best-fit estimate of the heritability of AUD was 0.49 [95% confidence interval (CI) 0.43-0.53], and the proportion of shared environmental variance was 0.10 (95% CI 0.03-0.16). Estimates of unique environmental proportions of variance differed significantly across studies. CONCLUSIONS: AUD is approximately 50% heritable. The multiple genetically informative studies of this syndrome have produced consistent results that support the validity of this heritability estimate, especially given the different potential methodological weaknesses of twin and adoption designs, and of assessments of AUD based on personal interviews v. official records. We also found evidence for modest shared environmental effects suggesting that environmental factors also contribute to the familial aggregation of AUDs.

Identification and validation of mixed anxiety-depression.

BACKGROUND: Mixed anxiety-depression (MAD) has been under scrutiny to determine its potential place in psychiatric nosology. The current study sought to investigate its prevalence, clinical characteristics, course and potential validators. METHOD: Restricted latent-class analyses were fit to 12-month self-reports of depression and anxiety symptom criteria in a large population-based sample of twins. Classes were examined across an array of relevant indicators (demographics, co-morbidity, adverse life events, clinical significance and twin concordance). Longitudinal analyses investigated the stability of, and transitions between, these classes for two time periods approximately 1.5 years apart. RESULTS: In all analyses, a class exhibiting levels of MAD symptomatology distinctly above the unaffected subjects yet having low prevalence of either major depression (MD) or generalized anxiety disorder (GAD) was identified. A restricted four-class model, constraining two classes to have no prior disorder history to distinguish residual or recurrent symptoms from new onsets in the last year, provided an interpretable classification: two groups with no prior history that were unaffected or had MAD and two with prior history having relatively low or high symptom levels. Prevalence of MAD was substantial (9-11%), and subjects with MAD differed quantitatively but not qualitatively from those with lifetime MD or GAD across the clinical validators examined. CONCLUSIONS: Our findings suggest that MAD is a commonly occurring, identifiable syndromal subtype that warrants further study and consideration for inclusion in future nosologic systems.

A longitudinal twin study of cluster A personality disorders.

BACKGROUND: While cluster A personality disorders (PDs) have been shown to be moderately heritable, we know little about the temporal stability of these genetic risk factors. METHOD: Paranoid PD (PPD) and schizotypal PD (STPD) were assessed using the Structured Interview for DSM-IV Personality in 2793 young adult twins from the Norwegian Institute of Public Health Twin Panel at wave 1 and 2282 twins on average 10 years later at wave 2. Using the program Mx, we fitted a longitudinal latent factor model using the number of endorsed criteria for PPD and STPD. RESULTS: The stability over time of the criteria counts for PPD and STPD, estimated as polychoric correlations, were +0.34 and +0.40, respectively. The best-fit longitudinal model included only additive genetic and individual-specific environmental factors with parameter estimates constrained to equality across the two waves. The cross-wave genetic and individual-specific environmental correlations for a latent cluster A factor were estimated to equal +1.00 and +0.13, respectively. The cross-time correlations for genetic and environmental effects specific to the individual PDs were estimated at +1.00 and +0.16-0.20, respectively. We found that 68% and 71% of the temporal stability of PPD and STPD derived, respectively, from the effect of genetic factors. CONCLUSION: Shared genetic risk factors for two of the cluster A PDs are highly stable in adults over a 10-year period while environmental risk factors are relatively transient. Over two-thirds of the long-term stability of the common cluster A PD liability can be attributed to genetic influences.

A longitudinal twin study of borderline and antisocial personality disorder traits in early to middle adulthood.

BACKGROUND: Antisocial personality disorder (ASPD) and borderline personality disorder (BPD) share genetic and environmental risk factors. Little is known about the temporal stability of these etiological factors in adulthood. METHOD: DSM-IV criteria for ASPD and BPD were assessed using structured interviews in 2282 Norwegian twins in early adulthood and again approximately 10 years later. Longitudinal biometric models were used to analyze the number of endorsed criteria. RESULTS: The mean criterion count for ASPD and BPD decreased 40% and 28%, respectively, from early to middle adulthood. Rank-order stability was 0.58 for ASPD and 0.45 for BPD. The best-fitting longitudinal twin model included only genetic and individual-specific environmental factors. Genetic effects, both those shared by ASPD and BPD, and those specific to each disorder remained completely stable. The unique environmental effects, however, changed substantially, with a correlation across time of 0.19 for the shared effects, and 0.39 and 0.15, respectively, for those specific to ASPD and BPD. Genetic effects accounted for 71% and 72% of the stability over time for ASPD and BPD, respectively. The genetic and environmental correlations between ASPD and BPD were 0.73, and 0.43, respectively, at both time points. CONCLUSION: ASPD and BPD traits were moderately stable from early to middle adulthood, mostly due to genetic risk factors which did not change over the 10-year assessment period. Environmental risk factors were mostly transient, and appear to be the main source of phenotypic change. Genetic liability factors were, to a large extent, shared by ASPD and BPD.

Heritable influences on amygdala and orbitofrontal cortex contribute to genetic variation in core dimensions of personality.

While many studies have reported that individual differences in personality traits are genetically influenced, the neurobiological bases mediating these influences have not yet been well characterized. To advance understanding concerning the pathway from genetic variation to personality, here we examined whether measures of heritable variation in neuroanatomical size in candidate regions (amygdala and medial orbitofrontal cortex) were associated with heritable effects on personality. A sample of 486 middle-aged (mean=55 years) male twins (complete MZ pairs=120; complete DZ pairs=84) underwent structural brain scans and also completed measures of two core domains of personality: positive and negative emotionality. After adjusting for estimated intracranial volume, significant phenotypic (r(p)) and genetic (r(g)) correlations were observed between left amygdala volume and positive emotionality (r(p)=.16, p<.01; r(g)=.23, p<.05, respectively). In addition, after adjusting for mean cortical thickness, genetic and nonshared-environmental correlations (r(e)) between left medial orbitofrontal cortex thickness and negative emotionality were also observed (r(g)=.34, p<.01; r(e)=-.19, p<.05, respectively). These findings support a model positing that heritable bases of personality are, at least in part, mediated through individual differences in the size of brain structures, although further work is still required to confirm this causal interpretation.

Evidence for multiple genetic factors underlying the DSM-IV criteria for alcohol dependence.

To determine the number of genetic factors underlying the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for alcohol dependence (AD), we conducted structural equation twin modeling for seven AD criteria, plus two summary screening questions, in 7133 personally interviewed male and female twins from the Virginia Adult Twin Study of Psychiatric and Substance Use Disorders, who reported lifetime alcohol consumption. The best-fit twin model required three genetic and two unique environmental common factors, and criterion-specific unique environmental factors. The first genetic factor was defined by high loadings for the probe question about quantity and frequency of alcohol consumption, and tolerance criterion. The second genetic factor loaded strongly on the probe question about self-recognition of alcohol-related problems and AD criteria for loss of control, desire to quit, preoccupation and activities given up. The third genetic factor had high loadings for withdrawal and continued use despite the problems criteria. Genetic factor scores derived from these three factors differentially predicted patterns of comorbidity, educational status and other historical/clinical features of AD. The DSM-IV syndrome of AD does not reflect a single dimension of genetic liability, rather, these criteria reflect three underlying dimensions that index risk for: (i) tolerance and heavy use; (ii) loss of control with alcohol associated social dysfunction and (iii) withdrawal and continued use despite problems. While tentative and in need of replication, these results, consistent with the rodent literature, were validated by examining predictions of the genetic factor scores and have implications for gene-finding efforts in AD.

Genetic and environmental contributions to the relationship between education and anxiety disorders - a twin study.

OBJECTIVE: To examine the negative statistical relationship between educational level and risk of anxiety disorders, and to estimate to what extent this relationship may be explained by genes or environmental factors influencing both phenotypes. METHOD: Registry data on educational level for 3339 young adult Norwegian twin pairs and diagnostic data on anxiety disorders for 1385 of these pairs were analysed, specifying structural equations models using MX software. RESULTS: In the best-fitting model, genes accounted for 59% of the variance in education. 18% of the variance was due to environmental factors shared by co-twins, and the remaining 23% due to non-shared environment; 46% of the variance in liability to anxiety disorders was genetic, the remaining variance was due to non-shared environment. A phenotypic polychoric correlation of -0.30 between educational level and 'any anxiety disorder' was estimated to be primarily (83% in the best-fitting model) caused by genes common to the two traits. CONCLUSION: The relationship between low education and risk of anxiety disorders appears to be primarily determined by genetic effect common to educational level and anxiety disorders.

Endophenotype: a conceptual analysis.

This paper provides a conceptual analysis of the endophenotype (EP) construct that is having an increasing role in genetic strategies for unraveling the etiology of psychiatric disorders (PDs). We make six major points illustrated through the method of path analysis. First, it is important to distinguish between mediational and liability-index (or 'risk indicator') models for EP, as only the former requires genetic risk for PD to pass through EP. Second, the relative reliability of EP and PD can have a critical role in the interpretation of results. Ignoring them can lead to substantial errors of inference. Third, we need to consider bidirectional relationships between an EP and a PD, and the possibility that genetic effects on PD are only partially mediated by EP. Fourth, EP models typically assume that all genetic effects that have an impact on EP also alter risk for PD. However, among the genetic influences on EP and PD, it is also plausible that some will influence only EP, some only PD and some both. Fifth, we should also consider models incorporating multiple EPs and PDs, which can be well captured by multivariate genetic methods. Sixth, EPs may also reflect the impact of the environment on risk for PDs. The EP concept has important potential lessons for etiological research in PDs that can be optimized by considering it as a special case of a broader set of multivariate genetic models, which can be fitted using currently available methodology.

Interleukin-1 region meta-analysis with osteoarthritis phenotypes.

OBJECTIVE: Several research groups have examined osteoarthritis (OA) association with Interleukin-1 (IL-1) region markers and haplotypes. The results have been suggestive for hand OA, negative for knee OA, and conflicting for hip OA. DESIGN: Our aim was to address conflicts employing meta-analytical methods on data from 1238 European-descent cases with various OA phenotypes and 1269 European-descent controls from four study centers. We imputed some missing genotype data and reconstructed IL-1 region extended haplotypes. A previously reported 7-marker IL1A-IL1B-IL1RN extended risk haplotype was tested for association with each specific index phenotype. RESULTS: For hip OA, data from three centers showed heterogeneity of extended-risk-haplotype effect, two panels showing trend toward risk and another showing protection, with overall odds ratio (OR) 1.24 (95% Confidence interval (CI) 0.45-3.41, P 0.67). The heterogeneity fell partly along control ascertainment lines, chiefly between controls ascertained as spouses of arthroplasty patients and controls identified through population radiographic survey. For knee OA, the results showed no heterogeneity and no significant extended-risk-haplotype effect. For hand OA, the results showed little heterogeneity and a modest trend toward positive association (summary OR 1.34, 95% CI 0.83-2.17 P 0.23). Using a Bayesian partition modeling approach, the 7-marker extended haplotypes showed no significant effect on any OA phenotype examined. A 3-single-nucleotide polymorphism (SNP) IL1B-IL1RN haplotype rs1143627-rs16944-rs419598 showed a trend toward hand OA association (posterior probability of association 0.72) with the most prominent feature being protection from a specific haplotype representing a partial mirror image of the extended risk haplotype (OR estimated at 0.46). CONCLUSIONS: The meta-analysis data do not confirm but only suggest that some hand and hip OA risk could be associated with the IL-1 region, particularly centered in IL1B and possibly also IL1RN.

Major depression and dimensional representations of DSM-IV personality disorders: a population-based twin study.

BACKGROUND: Major depressive disorder (MDD) co-occurs frequently with personality disorders (PDs). The extent to which this results from shared genetic or environmental risk factors remains uncertain. METHOD: Young adult twins (n=2801) from the population-based Norwegian Institute of Public Health Twin Panel were assessed at personal interview for DSM-IV lifetime MDD and the 10 Axis II PDs. The relationship between MDD and dimensional representations of all PDs was explored by stepwise logistic regression. Multivariate Cholesky twin models were fitted using the Mx program, and genetic and environmental correlations were estimated. RESULTS: Dimensional representations of borderline (BPD), avoidant (AVPD) and paranoid personality disorder (PPD) were independently and significantly associated with increased risk for MDD. Multivariate twin modeling indicated that one latent factor accounted for the genetic covariance between MDD and the three PDs. The genetic correlations between MDD and dimensional representations of BPD, AVPD and PPD were +0.56, +0.22 and +0.40 respectively. No sex differences or shared environmental effects were found. The structure of the individual-specific environmental factors influencing MDD and the three PDs were similar to the genetic factors but the environmental correlations were lower: +0.39, +0.23 and +0.27 respectively. CONCLUSIONS: There is substantial overlap between liability factors for MDD and BPD from cluster B, PPD from cluster A and AVPD from cluster C. The vulnerability to general PD pathology and MDD seem to be closely related. The patterns of co-morbidity observed between diverse psychiatric disorders might result from just a few liability factors.

A twin study of specific bulimia nervosa symptoms.

BACKGROUND: Twin studies have suggested that additive genetic factors significantly contribute to liability to bulimia nervosa (BN). However, the diagnostic criteria for BN remain controversial. In this study, an item-factor model was used to examine the BN diagnostic criteria and the genetic and environmental contributions to BN in a population-based twin sample. The validity of the equal environment assumption (EEA) for BN was also tested. METHOD: Participants were 1024 female twins (MZ n=614, DZ n=410) from the population-based Mid-Atlantic Twin Registry. BN was assessed using symptom-level (self-report) items consistent with DSM-IV and ICD-10 diagnostic criteria. Items assessing BN were included in an item-factor model. The EEA was measured by items assessing similarity of childhood and adolescent environment, which have demonstrated construct validity. Scores on the EEA factor were used to specify the degree to which twins shared environmental experiences in this model. RESULTS: The EEA was not violated for BN. Modeling results indicated that the majority of the variance in BN was due to additive genetic factors. There was substantial variability in additive genetic and environmental contributions to specific BN symptoms. Most notably, vomiting was very strongly influenced by additive genetic factors, while other symptoms were much less heritable, including the influence of weight on self-evaluation. These results highlight the importance of assessing eating disorders at the symptom level. CONCLUSIONS: Refinement of eating disorder phenotypes could ultimately lead to improvements in treatment and targeted prevention, by clarifying sources of variation for specific components of symptomatology.

Binge eating disorder: a symptom-level investigation of genetic and environmental influences on liability.

BACKGROUND: Recent behavioral genetic studies have emphasized the importance of investigating eating disorders at the level of individual symptoms, rather than as overall diagnoses. We examined the heritability of binge eating disorder (BED) using an item-factor analytic approach, which estimates contributions of additive genetic (A), common environmental (C), and unique environmental (E) influences on liability to BED as well as individual symptoms. METHOD: Participants were 614 monozygotic and 410 dizygotic same-sex female twins from the Mid-Atlantic Twin Registry who completed a self-report measure of BED symptoms based upon DSM-IV criteria. Genetic and environmental contributions to BED liability were assessed at the diagnostic and symptom levels, using an item-factor approach. RESULTS: Liability to BED was moderately heritable; 45% of the variance was due to A, with smaller proportions due to C (13%), and E (42%). Additive genetic effects accounted for 29-43% of the variance in individual items, while only 8-14% was due to C. CONCLUSIONS: Results highlight the relevance of examining eating disorders at the symptom level, rather than focusing on aggregate diagnoses.

A psychometric evaluation of the DSM-IV borderline personality disorder criteria: age and sex moderation of criterion functioning.

BACKGROUND: Despite its importance as a paradigmatic personality disorder, little is known about the measurement invariance of the DSM-IV borderline personality disorder (BPD) criteria; that is, whether the criteria assess the disorder equivalently across different groups. METHOD: BPD criteria were evaluated at interview in 2794 young adult Norwegian twins. Analyses, based on item-response modeling, were conducted to test for differential age and sex moderation of the individual BPD criteria characteristics given factor-level covariate effects. RESULTS: Confirmatory factor analytic results supported a unidimensional structure for the nine BPD criteria. Compared to males, females had a higher BPD factor mean, larger factor variance and there was a significant age by sex interaction on the factor mean. Strong differential sex and age by sex interaction effects were found for the 'impulsivity' criterion factor loading and threshold. Impulsivity related to the BPD factor poorly in young females but improved significantly in older females. Males reported more impulsivity compared to females and this difference increased with age. The 'affective instability' threshold was also moderated, with males reporting less than expected. CONCLUSIONS: The results suggest the DSM-IV BPD 'impulsivity' and 'affective instability' criteria function differentially with respect to age and sex, with impulsivity being especially problematic. If verified, these findings have important implications for the interpretation of prior research with these criteria. These non-invariant age and sex effects may be identifying criteria-level expression features relevant to BPD nosology and etiology. Criterion functioning assessed using modern psychometric methods should be considered in the development of DSM-V.

A whole genome association study of neuroticism using DNA pooling.

We describe a multistage approach to identify single nucleotide polymorphisms (SNPs) associated with neuroticism, a personality trait that shares genetic determinants with major depression and anxiety disorders. Whole genome association with 452 574 SNPs was performed on DNA pools from approximately 2000 individuals selected on extremes of neuroticism scores from a cohort of 88 142 people from southwest England. The most significant SNPs were then genotyped on independent samples to replicate findings. We were able to replicate association of one SNP within the PDE4D gene in a second sample collected by our laboratory and in a family-based test in an independent sample; however, the SNP was not significantly associated with neuroticism in two other independent samples. We also observed an enrichment of low P-values in known regions of copy number variations. Simulation indicates that our study had approximately 80% power to identify neuroticism loci in the genome with odds ratio (OR)>2, and approximately 50% power to identify small effects (OR=1.5). Since we failed to find any loci accounting for more than 1% of the variance, the heritability of neuroticism probably arises from many loci each explaining much less than 1%. Our findings argue the need for much larger samples than anticipated in genetic association studies and that the biological basis of emotional disorders is extremely complex.

Identification of genetically mediated cortical networks: a multivariate study of pediatric twins and siblings.

Structural magnetic resonance imaging data from 308 twins, 64 singleton siblings of twins, and 228 singletons were analyzed using structural equation modeling and selected multivariate methods to identify genetically mediated intracortical associations. Principal components analyses (PCA) of the genetic correlation matrix indicated a single factor accounting for over 60% of the genetic variability in cortical thickness. When covaried for mean global cortical thickness, PCA, cluster analyses, and graph models identified genetically mediated fronto-parietal and occipital networks. Graph theoretical models suggest that the observed genetically mediated relationships follow small world architectural rules. These findings are largely concordant with other multivariate studies of brain structure and function, the twin literature, and current understanding on the role of genes in cortical neurodevelopment.

Association study between the serotonin 1A receptor (HTR1A) gene and neuroticism, major depression, and anxiety disorders.

The serotonin neurotransmitter system in general, and the serotonin 1A receptor in particular, has been broadly implicated in the pathophysiology of mood and anxiety disorders, although the results of genetic association studies have been mixed. In this study, we examined the serotonin 1A receptor gene, HTR1A, for its association with shared genetic risk across a range of anxiety and depression-related phenotypes. Using multivariate structural equation modeling, we selected twin pairs from the population-based Virginia Adult Twin Study of Psychiatric and Substance Use Disorders scoring at the extremes of a latent genetic risk factor that underlies susceptibility to neuroticism, major depression, and several anxiety disorders. One member from each selected pair was entered into a 2-stage, case-control association study for the HTR1A gene. In the resulting sample of 589 cases and 539 controls, four SNPs spanning the HTR1A locus, including the C(-1019)G functional promoter polymorphism (rs6295), were screened in stage 1, the positive results of which were tested for replication in stage 2. While one marker met threshold significance criteria in stage 1, this association was not replicated in stage 2. Post-hoc analyses did not reveal association to any of the specific psychiatric phenotypes. Our data suggests that the HTR1A gene may not play a major role in the genetic susceptibility underlying depressive and anxiety-related phenotypes.