Strong Genetic Overlaps Between Dimensional and Categorical Models of Bipolar Disorders in a Family Sample.

Background: Bipolar disorder (BD) presents with a wide range of symptoms that vary among relatives, casting doubt on categorical illness models. To address this uncertainly, we investigated the heritability and genetic relationships between categorical and dimensional models of BD in a family sample. Methods: Participants in the Amish-Mennonite Bipolar Genetics (AMBiGen) study were assigned categorical mood disorder diagnoses by structured psychiatric interview and completed the Mood Disorder Questionnaire (MDQ), which assesses lifetime history of manic symptoms and associated impairment. Major MDQ dimensions were analyzed by Principal Component Analysis (PCA) in 726 participants. Heritability and genetic overlaps between categorical diagnoses and MDQ-derived dimensions were estimated with SOLAR-ECLIPSE within 432 genotyped participants. Results: MDQ scores were significantly higher among individuals diagnosed with BD and related disorders, as expected, but varied widely among relatives. PCA suggested a three-component model for the MDQ. Heritability of the MDQ score was 30% (p<0.001), evenly distributed across its three principal components. Strong and significant genetic correlations were found between categorical diagnoses and most MDQ measures. Limitations: Recruitment through probands with BD resulted in increased prevalence of BD in this sample, limiting generalizability. Unavailable genetic data reduced sample size for some analyses. Conclusion: heritability and high genetic correlations between categorical diagnoses and MDQ measures support a genetic continuity between dimensional and categorical models of BD.

Specificity of Psychiatric Polygenic Risk Scores and Their Effects on Associated Risk Phenotypes.

Background: Polygenic risk scores (PRSs) are indices of genetic liability for illness, but their clinical utility for predicting risk for a specific psychiatric disorder is limited. Genetic overlap among disorders and their effects on allied phenotypes may be a possible explanation, but this has been difficult to quantify given focus on singular disorders and/or allied phenotypes. Methods: We constructed PRSs for 5 psychiatric disorders (schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorder, attention-deficit/hyperactivity disorder) and 3 nonpsychiatric control traits (height, type II diabetes, irritable bowel disease) in the UK Biobank (N = 31,616) and quantified associations between PRSs and phenotypes allied with mental illness: behavioral (symptoms, cognition, trauma) and brain measures from magnetic resonance imaging. We then evaluated the extent of specificity among PRSs and their effects on these allied phenotypes. Results: Correlations among psychiatric PRSs replicated previous work, with overlap between schizophrenia and bipolar disorder, which was distinct from overlap between autism spectrum disorder and attention-deficit/hyperactivity disorder; overlap between psychiatric and control PRSs was minimal. There was, however, substantial overlap of PRS effects on allied phenotypes among psychiatric disorders and among psychiatric disorders and control traits, where the extent and pattern of overlap was phenotype specific. Conclusions: Results show that genetic distinctions between psychiatric disorders and between psychiatric disorders and control traits exist, but this does not extend to their effects on allied phenotypes. Although overlap can be informative, work is needed to construct PRSs that will function at the level of specificity needed for clinical application.

Cocktail-party listening and cognitive abilities show strong pleiotropy.

Introduction: The cocktail-party problem refers to the difficulty listeners face when trying to attend to relevant sounds that are mixed with irrelevant ones. Previous studies have shown that solving these problems relies on perceptual as well as cognitive processes. Previously, we showed that speech-reception thresholds (SRTs) on a cocktail-party listening task were influenced by genetic factors. Here, we estimated the degree to which these genetic factors overlapped with those influencing cognitive abilities. Methods: We measured SRTs and hearing thresholds (HTs) in 493 listeners, who ranged in age from 18 to 91 years old. The same individuals completed a cognitive test battery comprising 18 measures of various cognitive domains. Individuals belonged to large extended pedigrees, which allowed us to use variance component models to estimate the narrow-sense heritability of each trait, followed by phenotypic and genetic correlations between pairs of traits. Results: All traits were heritable. The phenotypic and genetic correlations between SRTs and HTs were modest, and only the phenotypic correlation was significant. By contrast, all genetic SRT-cognition correlations were strong and significantly different from 0. For some of these genetic correlations, the hypothesis of complete pleiotropy could not be rejected. Discussion: Overall, the results suggest that there was substantial genetic overlap between SRTs and a wide range of cognitive abilities, including abilities without a major auditory or verbal component. The findings highlight the important, yet sometimes overlooked, contribution of higher-order processes to solving the cocktail-party problem, raising an important caveat for future studies aiming to identify specific genetic factors that influence cocktail-party listening.

Impact of Copy Number Variants and Polygenic Risk Scores on Psychopathology in the UK Biobank.

BACKGROUND: Our understanding of the impact of copy number variants (CNVs) on psychopathology and their joint influence with polygenic risk scores (PRSs) remains limited. METHODS: The UK Biobank recruited 502,534 individuals ages 37 to 73 years living in the United Kingdom between 2006 and 2010. After quality control, genotype data from 459,855 individuals were available for CNV calling. A total of 61 commonly studied recurrent neuropsychiatric CNVs were selected for analyses and examined individually and in aggregate (any CNV, deletion, or duplication). CNV risk scores were used to quantify intolerance of CNVs to haploinsufficiency. Major depressive disorder and generalized anxiety disorder PRSs were generated for White British individuals (N = 408,870). Mood/anxiety factor scores were generated using item-level questionnaire data (N = 501,289). RESULTS: CNV carriers showed higher mood/anxiety scores than noncarriers, with the largest effects seen for intolerant deletions. A total of 11 individual deletions and 8 duplications were associated with higher mood/anxiety. Carriers of the 9p24.3 (DMRT1) duplication showed lower mood/anxiety. Associations remained significant for most CNVs when excluding individuals with psychiatric diagnoses. Nominally significant CNV × PRS interactions provided preliminary evidence that associations between select individual CNVs, but not CNVs in aggregate, and mood/anxiety may be modulated by PRSs. CONCLUSIONS: CNVs associated with risk for psychiatric disorders showed small to large effects on dimensional mood/anxiety scores in a general population cohort, even when excluding individuals with psychiatric diagnoses. CNV × PRS interactions showed that associations between select CNVs and mood/anxiety may be modulated by PRSs.

The Genetic contribution to solving the cocktail-party problem.

Communicating in everyday situations requires solving the cocktail-party problem, or segregating the acoustic mixture into its constituent sounds and attending to those of most interest. Humans show dramatic variation in this ability, leading some to experience real-world problems irrespective of whether they meet criteria for clinical hearing loss. Here, we estimated the genetic contribution to cocktail-party listening by measuring speech-reception thresholds (SRTs) in 425 people from large families and ranging in age from 18 to 91 years. Roughly half the variance of SRTs was explained by genes (h 2 = 0.567). The genetic correlation between SRTs and hearing thresholds (HTs) was medium (ρ G = 0.392), suggesting that the genetic factors influencing cocktail-party listening were partially distinct from those influencing sound sensitivity. Aging and socioeconomic status also strongly influenced SRTs. These findings may represent a first step toward identifying genes for "hidden hearing loss," or hearing problems in people with normal HTs.

Similar Rates of Deleterious Copy Number Variants in Early-Onset Psychosis and Autism Spectrum Disorder.

OBJECTIVE: Copy number variants (CNVs) are strongly associated with neurodevelopmental and psychotic disorders. Early-onset psychosis (EOP), where symptoms appear before 18 years of age, is thought to be more strongly influenced by genetic factors than adult-onset psychotic disorders. However, the prevalence and effect of CNVs in EOP is unclear. METHODS: The authors documented the prevalence of recurrent CNVs and the functional impact of deletions and duplications genome-wide in 137 children and adolescents with EOP compared with 5,540 individuals with autism spectrum disorder (ASD) and 16,504 population control subjects. Specifically, the frequency of 47 recurrent CNVs previously associated with neurodevelopmental and neuropsychiatric illnesses in each cohort were compared. Next, CNV risk scores (CRSs), indices reflecting the dosage sensitivity for any gene across the genome that is encapsulated in a deletion or duplication separately, were compared between groups. RESULTS: The prevalence of recurrent CNVs was significantly higher in the EOP group than in the ASD (odds ratio=2.30) and control (odds ratio=5.06) groups. However, the difference between the EOP and ASD groups was attenuated when EOP participants with co-occurring ASD were excluded. CRS was significantly higher in the EOP group compared with the control group for both deletions (odds ratio=1.30) and duplications (odds ratio=1.09). In contrast, the EOP and ASD groups did not differ significantly in terms of CRS. CONCLUSIONS: Given the high frequency of recurrent CNVs in the EOP group and comparable CRSs in the EOP and ASD groups, the findings suggest that all children and adolescents with a psychotic diagnosis should undergo genetic screening, as is recommended in ASD.

Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses: A Multisite Study of Multiplex Pedigrees.

BACKGROUND: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. METHODS: Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. RESULTS: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. CONCLUSIONS: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery.

Genetic influences on externalizing psychopathology overlap with cognitive functioning and show developmental variation.

BACKGROUND: Questions remain regarding whether genetic influences on early life psychopathology overlap with cognition and show developmental variation. METHODS: Using data from 9,421 individuals aged 8-21 from the Philadelphia Neurodevelopmental Cohort, factors of psychopathology were generated using a bifactor model of item-level data from a psychiatric interview. Five orthogonal factors were generated: anxious-misery (mood and anxiety), externalizing (attention deficit hyperactivity and conduct disorder), fear (phobias), psychosis-spectrum, and a general factor. Genetic analyses were conducted on a subsample of 4,662 individuals of European American ancestry. A genetic relatedness matrix was used to estimate heritability of these factors, and genetic correlations with executive function, episodic memory, complex reasoning, social cognition, motor speed, and general cognitive ability. Gene × Age analyses determined whether genetic influences on these factors show developmental variation. RESULTS: Externalizing was heritable (h2 = 0.46, p = 1 × 10-6), but not anxious-misery (h2 = 0.09, p = 0.183), fear (h2 = 0.04, p = 0.337), psychosis-spectrum (h2 = 0.00, p = 0.494), or general psychopathology (h2 = 0.21, p = 0.040). Externalizing showed genetic overlap with face memory (ρg = -0.412, p = 0.004), verbal reasoning (ρg = -0.485, p = 0.001), spatial reasoning (ρg = -0.426, p = 0.010), motor speed (ρg = 0.659, p = 1x10-4), verbal knowledge (ρg = -0.314, p = 0.002), and general cognitive ability (g)(ρg = -0.394, p = 0.002). Gene × Age analyses revealed decreasing genetic variance (γg = -0.146, p = 0.004) and increasing environmental variance (γe = 0.059, p = 0.009) on externalizing. CONCLUSIONS: Cognitive impairment may be a useful endophenotype of externalizing psychopathology and, therefore, help elucidate its pathophysiological underpinnings. Decreasing genetic variance suggests that gene discovery efforts may be more fruitful in children than adolescents or young adults.

Genetic influence on cognitive development between childhood and adulthood.

Successful cognitive development between childhood and adulthood has important consequences for future mental and physical wellbeing, as well as occupational and financial success. Therefore, delineating the genetic influences underlying changes in cognitive abilities during this developmental period will provide important insights into the biological mechanisms that govern both typical and atypical maturation. Using data from the Philadelphia Neurodevelopmental Cohort (PNC), a large population-based sample of individuals aged 8 to 21 years old (n = 6634), we used an empirical relatedness matrix to establish the heritability of general and specific cognitive functions and determine if genetic factors influence cognitive maturation (i.e., Gene × Age interactions) between childhood and early adulthood. We found that neurocognitive measures across childhood and early adulthood were significantly heritable. Moreover, genetic variance on general cognitive ability, or g, increased significantly between childhood and early adulthood. Finally, we did not find evidence for decay in genetic correlation on neurocognition throughout childhood and adulthood, suggesting that the same genetic factors underlie cognition at different ages throughout this developmental period. Establishing significant Gene × Age interactions in neurocognitive functions across childhood and early adulthood is a necessary first step in identifying genes that influence cognitive development, rather than genes that influence cognition per se. Moreover, since aberrant cognitive development confers risk for several psychiatric disorders, further examination of these Gene × Age interactions may provide important insights into their etiology.

Associations of cannabis use disorder with cognition, brain structure, and brain function in African Americans.

Although previous studies have highlighted associations of cannabis use with cognition and brain morphometry, critical questions remain with regard to the association between cannabis use and brain structural and functional connectivity. In a cross-sectional community sample of 205 African Americans (age 18-70) we tested for associations of cannabis use disorder (CUD, n = 57) with multi-domain cognitive measures and structural, diffusion, and resting state brain-imaging phenotypes. Post hoc model evidence was computed with Bayes factors (BF) and posterior probabilities of association (PPA) to account for multiple testing. General cognitive functioning, verbal intelligence, verbal memory, working memory, and motor speed were lower in the CUD group compared with non-users (p < .011; 1.9 < BF < 3,217). CUD was associated with altered functional connectivity in a network comprising the motor-hand region in the superior parietal gyri and the anterior insula (p < .04). These differences were not explained by alcohol, other drug use, or education. No associations with CUD were observed in cortical thickness, cortical surface area, subcortical or cerebellar volumes (0.12 < BF < 1.5), or graph-theoretical metrics of resting state connectivity (PPA < 0.01). In a large sample collected irrespective of cannabis used to minimize recruitment bias, we confirm the literature on poorer cognitive functioning in CUD, and an absence of volumetric brain differences between CUD and non-CUD. We did not find evidence for or against a disruption of structural connectivity, whereas we did find localized resting state functional dysconnectivity in CUD. There was sufficient proof, however, that organization of functional connectivity as determined via graph metrics does not differ between CUD and non-user group.

Genetic Contributions to Multivariate Data-Driven Brain Networks Constructed via Source-Based Morphometry.

Identifying genetic factors underlying neuroanatomical variation has been difficult. Traditional methods have used brain regions from predetermined parcellation schemes as phenotypes for genetic analyses, although these parcellations often do not reflect brain function and/or do not account for covariance between regions. We proposed that network-based phenotypes derived via source-based morphometry (SBM) may provide additional insight into the genetic architecture of neuroanatomy given its data-driven approach and consideration of covariance between voxels. We found that anatomical SBM networks constructed on ~ 20 000 individuals from the UK Biobank were heritable and shared functionally meaningful genetic overlap with each other. We additionally identified 27 unique genetic loci that contributed to one or more SBM networks. Both GWA and genetic correlation results indicated complex patterns of pleiotropy and polygenicity similar to other complex traits. Lastly, we found genetic overlap between a network related to the default mode and schizophrenia, a disorder commonly associated with neuroanatomic alterations.

Neurocognitive impairment in type 2 diabetes: evidence for shared genetic aetiology.

AIMS/HYPOTHESIS: Type 2 diabetes is associated with cognitive impairments, but it is unclear whether common genetic factors influence both type 2 diabetes risk and cognition. METHODS: Using data from 1892 Mexican-American individuals from extended pedigrees, including 402 with type 2 diabetes, we examined possible pleiotropy between type 2 diabetes and cognitive functioning, as measured by a comprehensive neuropsychological test battery. RESULTS: Negative phenotypic correlations (ρp) were observed between type 2 diabetes and measures of attention (Continuous Performance Test [CPT d']: ρp = -0.143, p = 0.001), verbal memory (California Verbal Learning Test [CVLT] recall: ρp = -0.111, p = 0.004) and face memory (Penn Face Memory Test [PFMT]: ρp = -0.127, p = 0.002; PFMT Delayed: ρp = -0.148, p = 2 × 10-4), replicating findings of cognitive impairment in type 2 diabetes. Negative genetic correlations (ρg) were also observed between type 2 diabetes and measures of attention (CPT d': ρg = -0.401, p = 0.001), working memory (digit span backward test: ρg = -0.380, p = 0.005), and face memory (PFMT: ρg = -0.476, p = 2 × 10-4; PFMT Delayed: ρg = -0.376, p = 0.005), suggesting that the same genetic factors underlying risk for type 2 diabetes also influence poor cognitive performance in these domains. Performance in these domains was also associated with type 2 diabetes risk using an endophenotype ranking value approach. Specifically, on measures of attention (CPT d': ß = -0.219, p = 0.005), working memory (digit span backward: ß = -0.326, p = 0.035), and face memory (PFMT: ß = -0.171, p = 0.023; PFMT Delayed: ß = -0.215, p = 0.005), individuals with type 2 diabetes showed the lowest performance, while unaffected/unrelated individuals showed the highest performance, and those related to an individual with type 2 diabetes performed at an intermediate level. CONCLUSIONS/INTERPRETATION: These findings suggest that cognitive impairment may be a useful endophenotype of type 2 diabetes and, therefore, help to elucidate the pathophysiological underpinnings of this chronic disease. DATA AVAILABILITY: The data analysed in this study is available in dbGaP: www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs001215.v2.p2.

Minimal Relationship between Local Gyrification and General Cognitive Ability in Humans.

Previous studies suggest that gyrification is associated with superior cognitive abilities in humans, but the strength of this relationship remains unclear. Here, in two samples of related individuals (total N = 2882), we calculated an index of local gyrification (LGI) at thousands of cortical surface points using structural brain images and an index of general cognitive ability (g) using performance on cognitive tests. Replicating previous studies, we found that phenotypic and genetic LGI-g correlations were positive and statistically significant in many cortical regions. However, all LGI-g correlations in both samples were extremely weak, regardless of whether they were significant or nonsignificant. For example, the median phenotypic LGI-g correlation was 0.05 in one sample and 0.10 in the other. These correlations were even weaker after adjusting for confounding neuroanatomical variables (intracranial volume and local cortical surface area). Furthermore, when all LGIs were considered together, at least 89% of the phenotypic variance of g remained unaccounted for. We conclude that the association between LGI and g is too weak to have profound implications for our understanding of the neurobiology of intelligence. This study highlights potential issues when focusing heavily on statistical significance rather than effect sizes in large-scale observational neuroimaging studies.

Cognitive impairment from early to middle adulthood in patients with affective and nonaffective psychotic disorders.

BACKGROUND: Cognitive impairment is a core feature of psychotic disorders, but the profile of impairment across adulthood, particularly in African-American populations, remains unclear. METHODS: Using cross-sectional data from a case-control study of African-American adults with affective (n = 59) and nonaffective (n = 68) psychotic disorders, we examined cognitive functioning between early and middle adulthood (ages 20-60) on measures of general cognitive ability, language, abstract reasoning, processing speed, executive function, verbal memory, and working memory. RESULTS: Both affective and nonaffective psychosis patients showed substantial and widespread cognitive impairments. However, comparison of cognitive functioning between controls and psychosis groups throughout early (ages 20-40) and middle (ages 40-60) adulthood also revealed age-associated group differences. During early adulthood, the nonaffective psychosis group showed increasing impairments with age on measures of general cognitive ability and executive function, while the affective psychosis group showed increasing impairment on a measure of language ability. Impairments on other cognitive measures remained mostly stable, although decreasing impairments on measures of processing speed, memory and working memory were also observed. CONCLUSIONS: These findings suggest similarities, but also differences in the profile of cognitive dysfunction in adults with affective and nonaffective psychotic disorders. Both affective and nonaffective patients showed substantial and relatively stable impairments across adulthood. The nonaffective group also showed increasing impairments with age in general and executive functions, and the affective group showed an increasing impairment in verbal functions, possibly suggesting different underlying etiopathogenic mechanisms.

Rediscovering the value of families for psychiatric genetics research.

As it is likely that both common and rare genetic variation are important for complex disease risk, studies that examine the full range of the allelic frequency distribution should be utilized to dissect the genetic influences on mental illness. The rate limiting factor for inferring an association between a variant and a phenotype is inevitably the total number of copies of the minor allele captured in the studied sample. For rare variation, with minor allele frequencies of 0.5% or less, very large samples of unrelated individuals are necessary to unambiguously associate a locus with an illness. Unfortunately, such large samples are often cost prohibitive. However, by using alternative analytic strategies and studying related individuals, particularly those from large multiplex families, it is possible to reduce the required sample size while maintaining statistical power. We contend that using whole genome sequence (WGS) in extended pedigrees provides a cost-effective strategy for psychiatric gene mapping that complements common variant approaches and WGS in unrelated individuals. This was our impetus for forming the "Pedigree-Based Whole Genome Sequencing of Affective and Psychotic Disorders" consortium. In this review, we provide a rationale for the use of WGS with pedigrees in modern psychiatric genetics research. We begin with a focused review of the current literature, followed by a short history of family-based research in psychiatry. Next, we describe several advantages of pedigrees for WGS research, including power estimates, methods for studying the environment, and endophenotypes. We conclude with a brief description of our consortium and its goals.

A QTL on chromosome 3q23 influences processing speed in humans.

Processing speed is a psychological construct that refers to the speed with which an individual can perform any cognitive operation. Processing speed correlates strongly with general cognitive ability, declines sharply with age and is impaired across a number of neurological and psychiatric disorders. Thus, identifying genes that influence processing speed will likely improve understanding of the genetics of intelligence, biological aging and the etiologies of numerous disorders. Previous genetics studies of processing speed have relied on simple phenotypes (eg, mean reaction time) derived from single tasks. This strategy assumes, erroneously, that processing speed is a unitary construct. In the present study, we aimed to characterize the genetic architecture of processing speed by using a multidimensional model applied to a battery of cognitive tasks. Linkage and QTL-specific association analyses were performed on the factors from this model. The randomly ascertained sample comprised 1291 Mexican-American individuals from extended pedigrees. We found that performance on all three distinct processing-speed factors (Psychomotor Speed; Sequencing and Shifting and Verbal Fluency) were moderately and significantly heritable. We identified a genome-wide significant quantitative trait locus (QTL) on chromosome 3q23 for Psychomotor Speed (LOD = 4.83). Within this locus, we identified a plausible and interesting candidate gene for Psychomotor Speed (Z = 2.90, P = 1.86 × 10-03 ).

Clinical correlates of subsyndromal depression in African American individuals with psychosis: The relationship with positive symptoms and comorbid substance dependence.

Patients with psychosis exhibit subsyndromal depressive symptoms during the course of illness and yet the clinical correlates of these symptoms remain under-investigated. We aimed to investigate the clinical correlates of subsyndromal depression in psychosis including the extent to which they mediate commonly observed comorbid substance dependence. We developed a model of depression in a non-clinical sample recruited via Amazon's Mechanical Turk (N = 266), and confirmed that model in a locally recruited African-American clinical sample comprising psychotic and non-psychotic individuals (N = 256). Using scores from this model we tested: the strength of relationships between depressive symptomatology and positive, negative and disorganized symptoms in a range of psychotic disorders; whether depressive symptoms were higher in individuals with affective psychoses versus schizophrenia; and if depressive symptomatology mediated the relationship between psychosis and substance dependence. Subsyndromal depressive symptomatology was significantly higher in individuals with psychosis than without psychosis, but did not significantly differ between affective and non-affective psychotic groups. Depressive symptomatology was significantly related to positive (but not negative or disorganized) psychotic symptoms, and mediated the relationship between psychosis and substance dependence. The present study underlines the importance of assessing subsyndromal depression in patients with psychosis, and generates a number of testable predictions for future work. In particular, the examination of the relationships between comorbid psychopathology, namely depression and substance abuse, may improve insight into the neurobiology of psychosis.

Disentangling the genetic overlap between cholesterol and suicide risk.

Suicide is major public health concern; one million individuals worldwide die by suicide each year of which there are many more attempts. Thus, it is imperative that robust and reliable indicators, or biomarkers, of suicide risk be identified so that individuals at risk can be identified and provided appropriate interventions as quickly as possible. Previous work has revealed a relationship between low levels of circulating cholesterol and suicide risk, implicating cholesterol level as one such potential biomarker, but the factors underlying this relationship remain unknown. In the present study, we applied a combination of bivariate polygenic and coefficient-of-relatedness analysis, followed by mediation analysis, in a large sample of Mexican-American individuals from extended pedigrees [N = 1897; 96 pedigrees (average size = 19.17 individuals, range = 2-189) 60% female; mean age = 42.58 years, range = 18-97 years, sd = 15.75 years] with no exclusion criteria for any given psychiatric disorder. We observed that total esterified cholesterol measured at the time of psychiatric assessment shared a significant genetic overlap with risk for suicide attempt (ρg = -0.64, p = 1.24 × 10-04). We also found that total unesterified cholesterol measured around 20 years prior to assessment varied as a function of genetic proximity to an affected individual (h2 = 0.21, se = 0.10, p = 8.73 × 10-04; ßsuicide = -0.70, se = 0.25, p = 8.90 × 10-03). Finally, we found that the relationship between total unesterified cholesterol and suicide risk was significantly mediated by ABCA-1-specific cholesterol efflux capacity (ßsuicide-efflux = -0.45, p = 0.039; ßefflux-cholexterol = -0.34, p < 0.0001; ßindirect = -0.15, p = 0.044). These findings suggest that the relatively well-delineated process of cholesterol metabolism and associated molecular pathways will be informative for understanding the neurobiological underpinnings of risk for suicide attempt.

Deficits in visual working-memory capacity and general cognition in African Americans with psychosis.

On average, patients with psychosis perform worse than controls on visual change-detection tasks, implying that psychosis is associated with reduced capacity of visual working memory (WM). In the present study, 79 patients diagnosed with various psychotic disorders and 166 controls, all African Americans, completed a change-detection task and several other neurocognitive measures. The aims of the study were to (1) determine whether we could observe a between-group difference in performance on the change-detection task in this sample; (2) establish whether such a difference could be specifically attributed to reduced WM capacity (k); and (3) estimate k in the context of the general cognitive deficit in psychosis. Consistent with previous studies, patients performed worse than controls on the change-detection task, on average. Bayesian hierarchical cognitive modeling of the data suggested that this between-group difference was driven by reduced k in patients, rather than differences in other psychologically meaningful model parameters (guessing behavior and lapse rate). Using the same modeling framework, we estimated the effect of psychosis on k while controlling for general intellectual ability (g, obtained from the other neurocognitive measures). The results suggested that reduced k in patients was stronger than predicted by the between-group difference in g. Moreover, a mediation analysis suggested that the relationship between psychosis and g (i.e., the general cognitive deficit) was mediated by k. The results were consistent with the idea that reduced k is a specific deficit in psychosis, which contributes to the general cognitive deficit.