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The insula and medial prefrontal cortex (mPFC) share functional, histological, transcriptional, and developmental characteristics, and they serve higher cognitive functions of theoretical relevance to schizophrenia and related disorders. Meta-analyses and multivariate analysis of structural magnetic resonance imaging (MRI) scans indicate that gray matter density and volume reductions in schizophrenia are the most consistent and pronounced in a network primarily composed of the insula and mPFC. We used source-based morphometry, a multivariate technique optimized for structural MRI, in a large sample of randomly ascertained pedigrees (N = 887) to derive an insula-mPFC component and to investigate its genetic determinants. Firstly, we replicated the insula-mPFC gray matter component as an independent source of gray matter variation in the general population, and verified its relevance to schizophrenia in an independent case-control sample. Secondly, we showed that the neuroanatomical variation defined by this component is largely determined by additive genetic variation (h(2) = 0.59), and genome-wide linkage analysis resulted in a significant linkage peak at 12q24 (LOD = 3.76). This region has been of significant interest to psychiatric genetics as it contains the Darier's disease locus and other proposed susceptibility genes (e.g., DAO, NOS1), and it has been linked to affective disorders and schizophrenia in multiple populations. Thus, in conjunction with previous clinical studies, our data imply that one or more psychiatric risk variants at 12q24 are co-inherited with reductions in mPFC and insula gray matter concentration. © 2015 Wiley Periodicals, Inc.

The role of the amygdala in emotion recognition is well established, and amygdala volume and emotion recognition performance have each been shown separately to be highly heritable traits, but the potential role of common genetic influences on both traits has not been explored. The authors investigated the pleiotropic influences of amygdala volume and emotion recognition performance.In a sample of randomly selected extended pedigrees (N=858), the authors used a combination of univariate and bivariate linkage to investigate pleiotropy between amygdala volume and emotion recognition performance and followed up with association analysis.The authors found a pleiotropic region for amygdala volume and emotion recognition performance on chromosome 4q26 (LOD score=4.40). Association analysis conducted in the region underlying the bivariate linkage peak revealed a variant meeting the corrected significance level (Bonferroni-corrected p=5.01×10(-5)) within an intron of PDE5A (rs2622497, p=4.4×10(-5)) as being jointly influential on both traits. PDE5A has been implicated previously in recognition-memory deficits and is expressed in subcortical structures that are thought to underlie memory ability, including the amygdala.This study extends our understanding of the shared etiology between the amygdala and emotion recognition by showing that the overlap between amygdala volume and emotion recognition performance is due at least in part to common genetic influences. Moreover, this study identifies a pleiotropic locus for the two traits and an associated variant, which localizes the genetic signal even more precisely. These results, when taken in the context of previous research, highlight the potential utility of PDE5 inhibitors for ameliorating emotion recognition deficits in individuals suffering from mental or neurodegenerative illness.

Background Although case-control approaches are beginning to disentangle schizophrenia’s complex polygenic burden, other methods will likely be necessary to fully identify and characterize risk genes. Endophenotypes, traits genetically correlated with an illness, can help characterize the impact of risk genes by providing genetically relevant traits that are more tractable than the behavioral symptoms that classify mental illness. Here, we present an analytic approach for discovering and empirically validating endophenotypes in extended pedigrees with very few affected individuals. Our approach indexes each family member’s risk as a function of shared genetic kinship with an affected individual, often referred to as the coefficient of relatedness. To demonstrate the utility of this approach, we search for neurocognitive and neuroanatomic endophenotypes for schizophrenia in large unselected multigenerational pedigrees. Methods A fixed-effects test within the variance component framework was performed on neurocognitive and cortical surface area traits in 1606 Mexican-American individuals from large, randomly ascertained extended pedigrees who participated in the Genetics of Brain Structure and Function study. As affecteds were excluded from analyses, results were not influenced by disease state or medication usage. Results Despite having sampled just 6 individuals with schizophrenia, our sample provided 233 individuals at various levels of genetic risk for the disorder. We identified three neurocognitive measures (digit-symbol substitution, facial memory, and emotion recognition) and six medial temporal and prefrontal cortical surfaces associated with liability for schizophrenia. Conclusions With our novel analytic approach, one can discover and rank endophenotypes for schizophrenia, or any heritable disease, in randomly ascertained pedigrees.

Bipolar illness is a debilitating neuropsychiatric disorder associated with alterations in the ventral anterior cingulate cortex (vACC), a brain region thought to regulate emotional behavior. Although recent data-driven functional connectivity studies provide evidence consistent with this possibility, the role of vACC in bipolar illness and its pattern of whole brain connectivity remain unknown. Furthermore, no study has established whether vACC exhibits differential whole brain connectivity in bipolar patients with and without co-occurring psychosis and whether this pattern resembles that found in schizophrenia. We conducted a human resting-state functional connectivity investigation focused on the vACC seed in 73 remitted bipolar I disorder patients (33 with psychosis history), 56 demographically matched healthy comparison subjects, and 73 demographically matched patients with chronic schizophrenia. Psychosis history within the bipolar disorder group corresponded with significant between-group connectivity alterations along the dorsal medial prefrontal surface when using the vACC seed. Patients with psychosis history showed reduced connectivity (Cohen's d = -0.69), whereas those without psychosis history showed increased vACC coupling (Cohen's d = 0.8) relative to controls. The vACC connectivity observed in chronic schizophrenia patients was not significantly different from that seen in bipolar patients with psychosis history but was significantly reduced compared with that in bipolar patients without psychosis history. These robust findings reveal complex vACC connectivity alterations in bipolar illness, which suggest differences depending on co-occurrence of lifetime psychosis. The similarities in vACC connectivity patterns in schizophrenia and psychotic bipolar disorder patients may suggest the existence of common mechanisms underlying psychotic symptoms in the two disorders.

Linkage studies of alcoholism have implicated several chromosome regions, leading to the successful identification of susceptibility genes, including ADH4 and GABRA2 on chromosome 4. Quantitative endophenotypes that are potentially closer to gene action than clinical endpoints offer a means of obtaining more refined linkage signals of genes that predispose alcohol use disorders (AUD). In this study we examine a self-reported measure of the maximum number of drinks consumed in a 24-hr period (abbreviated Max Drinks), a significantly heritable phenotype (h2 = 0.32 ± 0.05; P = 4.61 × 10−14) with a strong genetic correlation with AUD (ρg = 0.99 ± 0.13) for the San Antonio Family Study (n = 1,203). Genome-wide SNPs were analyzed using variance components linkage methods in the program SOLAR, revealing a novel, genome-wide significant QTL (LOD = 4.17; P = 5.85 × 10−6) for Max Drinks at chromosome 6p22.3, a region with a number of compelling candidate genes implicated in neuronal function and psychiatric illness. Joint analysis of Max Drinks and AUD status shows that the QTL has a significant non-zero effect on diagnosis (P = 4.04 × 10−3), accounting for 8.6% of the total variation. Significant SNP associations for Max Drinks were also identified at the linkage region, including one, rs7761213 (P = 2.14 × 10−4), obtained for an independent sample of Chinese families. Thus, our study identifies a potential risk locus for AUD at 6p22.3, with significant pleiotropic effects on the heaviness of alcohol consumption that may not be population specific. © 2014 Wiley Periodicals, Inc.

It is well established that risk for developing psychosis is largely mediated by the influence of genes, but identifying precisely which genes underlie that risk has been problematic. Focusing on endophenotypes, rather than illness risk, is one solution to this problem. Impaired cognition is a well-established endophenotype of psychosis. Here we aimed to characterize the genetic architecture of cognition using phenotypically detailed models as opposed to relying on general IQ or individual neuropsychological measures. In so doing we hoped to identify genes that mediate cognitive ability, which might also contribute to psychosis risk. Hierarchical factor models of genetically clustered cognitive traits were subjected to linkage analysis followed by QTL region-specific association analyses in a sample of 1,269 Mexican American individuals from extended pedigrees. We identified four genome wide significant QTLs, two for working and two for spatial memory, and a number of plausible and interesting candidate genes. The creation of detailed models of cognition seemingly enhanced the power to detect genetic effects on cognition and provided a number of possible candidate genes for psychosis.

Objective: Several lines of evidence indicate that white matter integrity is compromised in bipolar disorder, but the nature, extent, and biological causes remain elusive. To determine the extent to which white matter deficits in bipolar disorder are familial, the authors investigated white matter integrity in a large sample of bipolar patients, unaffected siblings, and healthy comparison subjects. Method: The authors collected diffusion imaging data for 64 adult bipolar patients, 60 unaffected siblings (including 54 discordant sibling pairs), and 46 demographically matched comparison subjects. Fractional anisotropy was compared between the groups using voxel-wise tract-based spatial statistics and by extracting mean fractional anisotropy from 10 regions of interest. Additionally, intraclass correlation coefficients were calculated between the sibling pairs as an index of familiality. Results: Widespread fractional anisotropy reductions in bipolar patients (>40,000 voxels) and more subtle reductions in their siblings, mainly restricted to the corpus callosum, posterior thalamic radiations, and left superior longitudinal fasciculus (>2,000 voxels) were observed. Similarly, region-of-interest analysis revealed significant reductions in most white matter regions in patients. In siblings, fractional anisotropy in the posterior thalamic radiation and the forceps was nominally reduced. Significant between-sibling correlations were found for mean fractional anisotropy across the tract-based spatial statistic skeleton, within significant clusters, and within nearly all regions of interest. Conclusions: These findings emphasize the relevance of white matter to neuropathology and familiality of bipolar disorder and encourage further use of white matter integrity markers as endophenotypes in genetic studies.

Psychiatric disorders are characterized by major fluctuations in psychological function over the course of weeks and months, but the dynamic characteristics of brain function over this timescale in healthy individuals are unknown. Here, as a proof of concept to address this question, we present the MyConnectome project. An intensive phenome-wide assessment of a single human was performed over a period of 18 months, including functional and structural brain connectivity using magnetic resonance imaging, psychological function and physical health, gene expression and metabolomics. A reproducible analysis workflow is provided, along with open access to the data and an online browser for results. We demonstrate dynamic changes in brain connectivity over the timescales of days to months, and relations between brain connectivity, gene expression and metabolites. This resource can serve as a testbed to study the joint dynamics of human brain and metabolic function over time, an approach that is critical for the development of precision medicine strategies for brain disorders., Large-scale, multimodal phenotypic characterisation is a valuable tool to explore brain function. Poldrack et al. collect and relate MRI, psychological, physiological, metabolic and gene expression data from a single human over an 18 month period, providing a rich resource for future studies.

Major depressive disorder (MDD) is a common and potentially life-threatening mood disorder. Identifying genetic markers for depression might provide reliable indicators of depression risk, which would, in turn, substantially improve detection, enabling earlier and more effective treatment. The aim of this study was to identify rare variants for depression, modeled as a continuous trait, using linkage and post-hoc association analysis. The sample comprised 1221 Mexican-American individuals from extended pedigrees. A single dimensional scale of MDD was derived using confirmatory factor analysis applied to all items from the Past Major Depressive Episode section of the Mini-International Neuropsychiatric Interview. Scores on this scale of depression were subjected to linkage analysis followed by QTL region-specific association analysis. Linkage analysis revealed a single genome-wide significant QTL (LOD = 3.43) on 10q26.13, QTL-specific association analysis conducted in the entire sample revealed a suggestive variant within an intron of the gene LHPP (rs11245316, p = 7.8×10-04; LD-adjusted Bonferroni-corrected p = 8.6×10-05). This region of the genome has previously been implicated in the etiology of MDD; the present study extends our understanding of the involvement of this region by highlighting a putative gene of interest (LHPP).

Previous work has shown that the hippocampus is smaller in the brains of individuals suffering from major depressive disorder (MDD) than those of healthy controls. Moreover, right hippocampal volume specifically has been found to predict the probability of subsequent depressive episodes. This study explored the utility of right hippocampal volume as an endophenotype of recurrent MDD (rMDD). We observed a significant genetic correlation between the two traits in a large sample of Mexican American individuals from extended pedigrees (ρg = -0.34, p = 0.013). A bivariate linkage scan revealed a significant pleiotropic quantitative trait locus on chromosome 18p11.31-32 (LOD = 3.61). Bivariate association analysis conducted under the linkage peak revealed a variant (rs574972) within an intron of the gene SMCHD1 meeting the corrected significance level (χ(2) = 19.0, p = 7.4 × 10(-5)). Univariate association analyses of each phenotype separately revealed that the same variant was significant for right hippocampal volume alone, and also revealed a suggestively significant variant (rs12455524) within the gene DLGAP1 for rMDD alone. The results implicate right-hemisphere hippocampal volume as a possible endophenotype of rMDD, and in so doing highlight a potential gene of interest for rMDD risk.

Diffusion tensor imaging studies show reductions in fractional anisotropy (FA) in individuals with bipolar disorder and their unaffected siblings. However, the use of various analysis methods is an important source of between-study heterogeneity. Using tract-based spatial statistics, we previously demonstrated widespread FA reductions in patients and unaffected relatives. To better interpret the neuroanatomical pattern of this previous finding and to assess the influence of methodological heterogeneity, we here applied tractography to the same sample.Diffusion-weighted images were acquired for 96 patients, 69 unaffected siblings and 56 controls. We applied TRACULA, an extension of a global probabilistic tractography algorithm, to automatically segment 18 major fiber tracts. Average FA within each tract and at each cross-section along each tract was compared between groups.Patients had reduced FA compared to healthy controls and their unaffected siblings in general, and in particular in the parietal part of the superior longitudinal fasciculus. In unaffected siblings, FA was nominally reduced compared to controls in the corpus callosum. Point-wise analyses indicated that similar effects were present along extended sections, but with variable effect sizes. Current symptom severity negatively correlated with FA in several fronto-limbic association tracts.The differential sensitivity of analysis techniques likely explains between-study heterogeneity in anatomical localization of FA reductions. The present tractography analysis confirms the presence of overall FA reductions in patients with bipolar disorder, which are most pronounced in the superior longitudinal fasciculus. Unaffected siblings may display similar, albeit more subtle and anatomically restricted FA reductions. Hum Brain Mapp 37:3474-3485, 2016. © 2016 Wiley Periodicals, Inc.

Alcohol abuse and dependence (alcohol use disorders, AUDs) are associated with brain shrinkage. Subcortical structures including the amygdala, hippocampus, ventral striatum, dorsal striatum, and thalamus subserve reward functioning and may be particularly vulnerable to alcohol-related damage. These structures may also show pre-existing deficits impacting the development and maintenance of AUD. It remains unclear whether there are common genetic features underlying both subcortical volumes and AUD. In this study, structural brain images were acquired from 872 Mexican-American individuals from extended pedigrees. Subcortical volumes were obtained using FreeSurfer, and quantitative genetic analyses were performed in SOLAR. We hypothesized the following: (1) reduced subcortical volumes in individuals with lifetime AUD relative to unrelated controls; (2) reduced subcortical volumes in individuals with current relative to past AUD; (3) in non-AUD individuals, reduced subcortical volumes in those with a family history of AUD compared to those without; and (4) evidence for common genetic underpinnings (pleiotropy) between AUD risk and subcortical volumes. Results showed that individuals with lifetime AUD showed larger ventricular and smaller amygdala volumes compared to non-AUD individuals. For the amygdala, there were no differences in volume between current vs past AUD, and non-AUD individuals with a family history of AUD demonstrated reductions compared to those with no such family history. Finally, amygdala volume was genetically correlated with the risk for AUD. Together, these results suggest that reduced amygdala volume reflects a pre-existing difference rather than alcohol-induced neurotoxic damage. Our genetic correlation analysis provides evidence for a common genetic factor underlying both reduced amygdala volumes and AUD risk.

It is now well established that regional indices of brain structure such as cortical thickness, surface area or grey matter volume exhibit spatially variable patterns of heritability. However, a recent study found these patterns to change with age during development, a result supported by gene expression studies. Changes in heritability have not been investigated in adulthood so far and could have important implications in the study of heritability and genetic correlations in the brain as well as in the discovery of specific genes explaining them. Herein, we tested for genotype by age (G × A) interactions, an extension of genotype by environment interactions, through adulthood and healthy aging in 902 subjects from the Genetics of Brain Structure (GOBS) study. A “jackknife” based method for the analysis of stable cortical thickness clusters (JASC) and scale selection is also introduced. Although additive genetic variance remained constant throughout adulthood, we found evidence for incomplete pleiotropy across age in the cortical thickness of paralimbic and parieto-temporal areas. This suggests that different genetic factors account for cortical thickness heritability at different ages in these regions.

We report effects of age, age2, sex and additive genetic effects on variability in gray matter thickness, surface area and white matter integrity in 1,010 subjects from the Genetics of Brain Structure and Function Study. Age was primarily associated with gray matter thickness and fractional anisotropy of water diffusion in white matter tracts, while sex was primarily associated with affected gray matter surface area; age2 was only significantly associated with average white matter integrity. Widespread heritability of neuroanatomic traits was observed, suggesting that brain structure is under strong genetic control. Furthermore, our findings indicate that neuroimaging-based measurements of cerebral variability are sensitive to genetic mediation. Further fundamental studies of genetic influence on the brain will help inform gene discovery initiatives in both clinical and normative samples.

Genetic and environmental influences on brain morphology were assessed in an extended-pedigree design by extracting depth-position profiles (DPP) of the central sulcus (CS). T1-weighted magnetic resonance images were used to measure CS length and depth in 467 human subjects from 35 extended families. Three primary forms of DPPs were observed. The most prevalent form, present in 70% of subjects, was bimodal, with peaks near hand and mouth regions. Trimodal and unimodal configurations accounted for 15 and 8%, respectively. Genetic control accounted for 56 and 66% of between-subject variance in average CS depth and length, respectively, and was not significantly influenced by environmental factors. Genetic control over CS depth ranged from 1 to 50% across the DPP. Areas of peak heritability occurred at locations corresponding to hand and mouth areas. Left and right analogous CS depth measurements were strongly pleiotropic. Shared genetic influence lessened as the distance between depth measurements was increased. We argue that DPPs are powerful phenotypes that should inform genetic influence of more complex brain regions and contribute to gene discovery efforts.

Background/Aims: Obesity is a major contributor to the global burden of chronic disease and disability, though current knowledge of causal biologic underpinnings is lacking. Through the regulation of energy homeostasis and interactions with adiposity and gut signals, the brain is thought to play a significant role in the development of this disorder. While neuroanatomical variation has been associated with obesity, it is unclear if this relationship is influenced by common genetic mechanisms. In this study, we sought genetic components that influence both brain anatomy and body mass index (BMI) to provide further insight into the role of the brain in energy homeostasis and obesity. Methods: MRI images of brain anatomy were acquired in 839 Mexican American individuals from large extended pedigrees. Bivariate linkage and quantitative analyses were performed in SOLAR. Results: Genetic factors associated with an increased BMI were also associated with a reduced cortical surface area and subcortical volume. We identified two genome-wide quantitative trait loci that influenced BMI and the ventral diencephalon volume, and BMI and the supramarginal gyrus surface area, respectively. Conclusions: This study represents the first genetic analysis seeking evidence of pleiotropic effects acting on both brain anatomy and BMI. Our results suggest that a region on chromosome 17 contributes to the development of obesity, potentially through leptin-induced signaling in the hypothalamus, and that a region on chromosome 3 appears to jointly influence the food-related reward circuitry and the supramarginal gyrus.

The human behavioral repertoire greatly exceeds that of nonhuman primates. Anatomical specializations of the human brain include an enlarged neocortex and prefrontal cortex (Semendeferi et al. in Am J Phys Anthropol 114:224–241, 2001), but regional enlargements alone cannot account for these vast functional differences. Hemispheric specialization has long believed to be a major contributing factor to such distinctive human characteristics as motor dominance, attentional control and language. Yet structural cerebral asymmetries, documented in both humans and some nonhuman primate species, are relatively minor compared to behavioral lateralization. Identifying the mechanisms that underlie these functional differences remains a goal of considerable interest. Here, we investigate the intrinsic connectivity networks in four primate species (humans, chimpanzees, baboons, and capuchin monkeys) using resting-state fMRI to evaluate the intra- and inter- hemispheric coherences of spontaneous BOLD fluctuation. All three nonhuman primate species displayed lateralized functional networks that were strikingly similar to those observed in humans. However, only humans had multi-region lateralized networks, which provide fronto-parietal connectivity. Our results indicate that this pattern of within-hemisphere connectivity distinguishes humans from nonhuman primates.

Automated image analysis of the brain should include measures of fundamental structural features such as size and shape. We used principal axes (P-A) measurements to measure overall size and shape of brain structures segmented from MR brain images. The rationale was that quantitative volumetric studies of brain structures would benefit from shape standardization as had been shown for whole brain studies. P-A analysis software was extended to include controls for variability in position and orientation to support individual structure spatial normalization (ISSN). The rationale was that ISSN would provide a bias-free means to remove elementary sources of a structure’s spatial variability in preparation for more detailed analyses. We studied nine brain structures (whole brain, cerebral hemispheres, cerebellum, brainstem, caudate, putamen, hippocampus, inferior frontal gyrus, and precuneus) from the 40-brain LPBA40 atlas. This paper provides the first report of anatomical positions and principal axes orientations within a standard reference frame, in addition to “shape/size related” principal axes measures, for the nine brain structures from the LPBA40 atlas. Analysis showed that overall size (mean volume) for internal brain structures was preserved using shape standardization while variance was reduced by more than 50%. Shape standardization provides increased statistical power for between-group volumetric studies of brain structures compared to volumetric studies that control only for whole brain size. To test ISSN’s ability to control for spatial variability of brain structures we evaluated the overlap of 40 regions of interest (ROIs) in a standard reference frame for the nine different brain structures before and after processing. Standardizations of orientation or shape were ineffective when not combined with position standardization. The greatest reduction in spatial variability was seen for combined standardizations of position, orientation and shape. These results show that ISSNs automated processing can be a valuable asset for measuring and controlling variability of fundamental features of brain structures.