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A primary goal of psychiatry is to better understand the pathways that link genetic risk to psychiatric symptoms. Here, we tested association of diagnosis and endophenotypes with overall and neurotransmitter pathway-specific polygenic risk in patients with early-stage psychosis. Subjects included 205 demographically diverse cases with a psychotic disorder who underwent comprehensive psychiatric and neurological phenotyping and 115 matched controls. Following genotyping, we calculated polygenic scores (PGSs) for schizophrenia (SZ) and bipolar disorder (BP) using Psychiatric Genomics Consortium GWAS summary statistics. To test if overall genetic risk can be partitioned into affected neurotransmitter pathways, we calculated pathway PGSs (pPGSs) for SZ risk affecting each of four major neurotransmitter systems: glutamate, GABA, dopamine, and serotonin. Psychosis subjects had elevated SZ PGS versus controls; cases with SZ or BP diagnoses had stronger SZ or BP risk, respectively. There was no significant association within psychosis cases between individual symptom measures and overall PGS. However, neurotransmitter-specific pPGSs were moderately associated with specific endophenotypes; notably, glutamate was associated with SZ diagnosis and with deficits in cognitive control during task-based fMRI, while dopamine was associated with global functioning. Finally, unbiased endophenotype-driven clustering identified three diagnostically mixed case groups that separated on primary deficits of positive symptoms, negative symptoms, global functioning, and cognitive control. All clusters showed strong genome-wide risk. Cluster 2, characterized by deficits in cognitive control and negative symptoms, additionally showed specific risk concentrated in glutamatergic and GABAergic pathways. Due to the intensive characterization of our subjects, the present study was limited to a relatively small cohort. As such, results should be followed up with additional research at the population and mechanism level. Our study suggests pathway-based PGS analysis may be a powerful path forward to study genetic mechanisms driving psychiatric endophenotypes.

Gastrointestinal (GI) disruptions and inflammatory bowel disease (IBD) are commonly associated with Parkinsons disease (PD), but how they may impact risk for PD remains poorly understood. Herein, we provide evidence that prodromal intestinal inflammation expedites and exacerbates PD endophenotypes in rodent carriers of the human PD risk allele LRRK2 G2019S in a sex-dependent manner. Chronic intestinal damage in genetically predisposed male mice promotes α-synuclein aggregation in the substantia nigra, loss of dopaminergic neurons and motor impairment. This male bias is preserved in gonadectomized males, and similarly conferred by sex chromosomal complement in gonadal females expressing human LRRK2 G2019S. The early onset and heightened severity of neuropathological and behavioral outcomes in male LRRK2 G2019S mice is preceded by increases in α-synuclein in the colon, α-synuclein-positive macrophages in the colonic lamina propria, and loads of phosphorylated α-synuclein within microglia in the substantia nigra. Taken together, these data reveal that prodromal intestinal inflammation promotes the pathogenesis of PD endophenotypes in male carriers of LRRK2 G2019S, through mechanisms that depend on genotypic sex and involve early accumulation of α-synuclein in myeloid cells within the gut.

microRNAs (miRNAs) have a broad influence on gene expression; however, we have limited insights into their contribution to rate of cognitive decline over time or Alzheimer's disease (AD). Given this, we tested associations of 528 miRNAs with cognitive trajectory, AD hallmark pathologies, and AD clinical diagnosis using small RNA sequencing from the dorsolateral prefrontal cortex of 641 community-based donors. We found 311 miRNAs differentially expressed in AD or its endophenotypes after adjusting for technical and sociodemographic variables. Among these, 137 miRNAs remained differentially expressed after additionally adjusting for several co-occurring age-related cerebral pathologies, suggesting that some miRNAs are associated with the traits through co-occurring pathologies while others through mechanisms independent from pathologies. Pathway enrichment analysis of downstream targets of these differentially expressed miRNAs found enrichment in transcription, postsynaptic signalling, cellular senescence, and lipoproteins. In sex-stratified analyses, five miRNAs showed sex-biased differential expression for one or more AD endophenotypes, highlighting the role that sex has in AD. Lastly, we used Mendelian randomization to test whether the identified differentially expressed miRNAs contribute to the cause or are the consequence of the traits. Remarkably, 15 differentially expressed miRNAs had evidence consistent with a causal role, laying the groundwork for future mechanistic studies of miRNAs in AD and its endophenotypes.

Treatment of youth concussion during the acute phase continues to evolve, and this has led to the emergence of guidelines to direct care. While symptoms after concussion typically resolve in 14-28 days, a portion (∼20%) of adolescents endorse persistent post-concussive symptoms (PPCS) beyond normal resolution. This report outlines a study implemented in response to the National Institute of Neurological Diseases and Stroke call for the development and initial clinical validation of objective biological measures to predict risk of PPCS in adolescents. We describe our plans for recruitment of a Development cohort of 11- to 17-year-old youth with concussion, and collection of autonomic, neurocognitive, biofluid, and imaging biomarkers. The most promising of these measures will then be validated in a separate Validation cohort of youth with concussion, and a final, clinically useful algorithm will be developed and disseminated. Upon completion of this study, we will have generated a battery of measures predictive of high risk for PPCS, which will allow for identification and testing of interventions to prevent PPCS in the most high-risk youth.

BackgroundAlzheimer's disease and related dementias (ADRD) involve biological processes that begin years to decades before onset of clinical symptoms. The plasma proteome can offer insight into brain aging and risk of incident dementia among cognitively healthy adults.ObjectiveTo identify biomarkers and biological pathways associated with neuroimaging measures and incident dementia in two large community-based cohorts by applying a correlation-based network analysis to the plasma proteome.MethodsWeighted co-expression network analysis of 1,305 plasma proteins identified four modules of co-expressed proteins, which were related to MRI brain volumes and risk of incident dementia over a median 20-year follow-up in Framingham Heart Study (FHS) Offspring cohort participants (n = 1,861). Analyses were replicated in the Cardiovascular Health Study (CHS) (n = 2,117, mean 6-year follow-up).ResultsTwo proteomic modules, one related to protein clearance and synaptic maintenance (M2) and a second to inflammation (M4), were associated with total brain volume in FHS (M2: p = 0.014; M4: p = 4.2×10-5). These modules were not significantly associated with hippocampal volume, white matter hyperintensities, or incident all-cause or AD dementia. Associations with TCBV did not replicate in CHS, an older cohort with a greater burden of comorbidities.ConclusionsProteome networks implicate an early role for biological pathways involving inflammation and synaptic function in preclinical brain atrophy, with implications for clinical dementia.

ObjectiveThe aim of this study was to catalog and evaluate response biomarkers correlated with autism spectrum disorder (ASD) symptoms to improve clinical trials.MethodsA systematic review of MEDLINE, Embase, and Scopus was conducted in April 2020. Seven criteria were applied to focus on original research that includes quantifiable response biomarkers measured alongside ASD symptoms. Interventional studies or human studies that assessed the correlation between biomarkers and ASD-related behavioral measures were included.ResultsA total of 5,799 independent records yielded 280 articles for review that reported on 940 biomarkers, 755 of which were unique to a single publication. Molecular biomarkers were the most frequently assayed, including cytokines, growth factors, measures of oxidative stress, neurotransmitters, and hormones, followed by neurophysiology (e.g., EEG and eye tracking), neuroimaging (e.g., functional MRI), and other physiological measures. Studies were highly heterogeneous, including in phenotypes, demographic characteristics, tissues assayed, and methods for biomarker detection. With a median total sample size of 64, almost all of the reviewed studies were only powered to identify biomarkers with large effect sizes. Reporting of individual-level values and summary statistics was inconsistent, hampering mega- and meta-analysis. Biomarkers assayed in multiple studies yielded mostly inconsistent results, revealing a "replication crisis."ConclusionsThere is currently no response biomarker with sufficient evidence to inform ASD clinical trials. This review highlights methodological imperatives for ASD biomarker research necessary to make definitive progress: consistent experimental design, correction for multiple comparisons, formal replication, sharing of sample-level data, and preregistration of study designs. Systematic "big data" analyses of multiple potential biomarkers could accelerate discovery.

The unique contribution of the serotonin transporter-linked polymorphic region (5-HTTLPR), intronic region 2 (STin2), and monoamine oxidase A (MAO-A) genes to individual differences in personality traits has been widely explored, and research has shown that certain forms of these polymorphisms relate to impulsivity and impulsivity-related disorders. Humans showing these traits are also described as having an asymmetrical prefrontal cortical activity when compared to others. In this explorative study, we examine the relationship between serotonergic neurotransmission polymorphisms, cortical activity features (prefrontal alpha asymmetry, individual alpha peak frequency [iAPF]), emotion-related and non-emotion-related impulsivity in humans. 5-HTTLPR, MAO-A, and STin2 polymorphisms were assessed in blood taken from 91 participants with high emotion-related impulsivity levels. Sixty-seven participants completed resting electroencephalography and a more comprehensive impulsivity index. In univariate analyses, iAPF correlated with both forms of emotion-related impulsivity. In multiple linear regression models, 5-HTTLPR polymorphism (model 1, adj. R2 = 15.2%) and iAPF were significant interacting predictors of emotion-related impulsivity, explaining a large share of the results' variance (model 2, adj. R2 = 21.2%). Carriers of the low transcriptional activity 5-HTTPLR and MAO-A phenotypes obtained higher emotion-related impulsivity scores than others did. No significant results were detected for non-emotion-related impulsivity or for a form of emotion-related impulsivity involving cognitive/motivational reactivity to emotion. Our findings support an endophenotypic approach to impulsivity, showing that tri-allelic 5-HTTLPR polymorphism, iAPF, and their interaction are relevant predictors of one form of emotion-related impulsivity.

ObjectivePatients show substantial differences in response to rehabilitation therapy after stroke. We hypothesized that specific genetic profiles might explain some of this variance and, secondarily, that genetic factors are related to cerebral atrophy post-stroke.MethodsThe phase 3 ICARE study examined response to motor rehabilitation therapies. In 216 ICARE enrollees, DNA was analyzed for presence of the BDNF val66met and the ApoE ε4 polymorphism. The relationship of polymorphism status to 12-month change in motor status (Wolf Motor Function Test, WMFT) was examined. Neuroimaging data were also evaluated (n=127).ResultsSubjects were 61±13 years old (mean±SD) and enrolled 43±22 days post-stroke; 19.7% were BDNF val66met carriers and 29.8% ApoE ε4 carriers. Carrier status for each polymorphism was not associated with WMFT, either at baseline or over 12 months of follow-up. Neuroimaging, acquired 5±11 days post-stroke, showed that BDNF val66met polymorphism carriers had a 1.34-greater degree of cerebral atrophy compared to non-carriers (P=.01). Post hoc analysis found that age of stroke onset was 4.6 years younger in subjects with the ApoE ε4 polymorphism (P=.02).ConclusionNeither the val66met BDNF nor ApoE ε4 polymorphism explained inter-subject differences in response to rehabilitation therapy. The BDNF val66met polymorphism was associated with cerebral atrophy at baseline, echoing findings in healthy subjects, and suggesting an endophenotype. The ApoE ε4 polymorphism was associated with younger age at stroke onset, echoing findings in Alzheimer's disease and suggesting a common biology. Genetic associations provide insights useful to understanding the biology of outcomes after stroke.

Accurate and efficient classification of variant pathogenicity is critical for research and clinical care. Using data from three large studies, we demonstrate that population-based associations between rare variants and quantitative endophenotypes for three monogenic diseases (low-density-lipoprotein cholesterol for familial hypercholesterolemia, electrocardiographic QTc interval for long QT syndrome, and glycosylated hemoglobin for maturity-onset diabetes of the young) provide evidence for variant pathogenicity. Effect sizes are associated with pathogenic ClinVar assertions (P

Copy Number Variants (CNVs) are associated with elevated rates of neuropsychiatric disorders. A 'genetics-first' approach, involving the CNV effects on the brain, irrespective of clinical symptomatology, allows investigation of mechanisms underlying neuropsychiatric disorders in the general population. Recent years have seen an increasing number of larger multisite neuroimaging studies investigating the effect of CNVs on structural and functional brain endophenotypes. Alterations overlap with those found in idiopathic psychiatric conditions but effect sizes are twofold to fivefold larger. Here we review new CNV-associated structural and functional brain alterations and outline the future of neuroimaging genomics research, with particular emphasis on developing new resources for the study of high-risk CNVs and rare genomic variants.

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

Over the last decade, genome-wide association studies of psychiatric disorders have identified numerous significant loci. Whereas these studies initially depended on cohorts ascertained for specific disorders, there has been a gradual shift in the ascertainment strategy toward population-based cohorts for which both genotype and heterogeneous phenotypic information are available. One of the advantages of population-based cohorts is that, in addition to clinical diagnoses and various proxies for diagnoses ('minimal phenotyping'), many of them also provide non-clinical phenotypes, including putative endophenotypes, that can be used to study domains of normal function in addition to, or instead of, clinical diagnoses. By studying endophenotypes it is possible to both dissect psychiatric disorders ('splitting') and to combine multiple phenotypes ('clumping'), which can either reinforce or challenge traditional diagnostic categories. Such endophenotypes may also permit a deeper exploration of the neurobiology of psychiatric disorders. A coordinated effort to fully exploit the potential of endophenotypes is overdue.

ImportanceThe Consortium on the Genetics of Schizophrenia (COGS) uses quantitative neurophysiological and neurocognitive endophenotypes with demonstrated deficits in schizophrenia as a platform from which to explore the underlying neural circuitry and genetic architecture. Many of these endophenotypes are associated with poor functional outcome in schizophrenia. Some are also endorsed as potential treatment targets by the US Food and Drug Administration.ObjectiveTo build on prior assessments of heritability, association, and linkage in the COGS phase 1 (COGS-1) families by reporting a genome-wide association study (GWAS) of 11 schizophrenia-related endophenotypes in the independent phase 2 (COGS-2) cohort of patients with schizophrenia and healthy comparison participants (HCPs).Design, setting, and participantsA total of 1789 patients with schizophrenia and HCPs of self-reported European or Latino ancestry were recruited through a collaborative effort across the COGS sites and genotyped using the PsychChip. Standard quality control filters were applied, and more than 6.2 million variants with a genotyping call rate of greater than 0.99 were available after imputation. Association was performed for data sets stratified by diagnosis and ancestry using linear regression and adjusting for age, sex, and 5 principal components, with results combined through weighted meta-analysis. Data for COGS-1 were collected from January 6, 2003, to August 6, 2008; data for COGS-2, from June 30, 2010, to February 14, 2014. Data were analyzed from October 28, 2016, to May 4, 2018.Main outcomes and measuresA genome-wide association study was performed to evaluate association for 11 neurophysiological and neurocognitive endophenotypes targeting key domains of schizophrenia related to inhibition, attention, vigilance, learning, working memory, executive function, episodic memory, and social cognition.ResultsThe final sample of 1533 participants included 861 male participants (56.2%), and the mean (SD) age was 41.8 (13.6) years. In total, 7 genome-wide significant regions (P

Increasingly, obstructive sleep apnea treatment is being recognized as amenable to a precision medicine approach. Many pathophysiologic mechanisms (endotypes) beyond anatomic compromise have now been identified and are readily determined during polysomnography, although randomized controlled trials of endotype-specific therapies are needed. Research indicates that endotypes may also be important in predicting both adherence to therapy and disease consequences (phenotypes). Biomarker discovery and Big Data approaches derived from wearable technology are areas of active investigation and may allow more robust conclusions to be drawn over time, such that patients may soon fully realize the benefits from fresh insights into sleep science.

The motor system in its manifold articulations is receiving increasing clinical and research attention. This is because motor impairments constitute a central, expressive component of the mental state examination and a key transdiagnostic feature indexing disease severity. Furthermore, within the schizophrenia spectrum, the integration of neurophysiological, developmental, and phenomenological perspectives suggests that motor impairment is not simply a generic, extrinsic proxy of an altered neurodevelopment, but might be more intimately related to psychotic risk. Therefore, an increased understanding, conceptualization, and knowledge of such motor system and its anomalies could empower contemporary risk prediction and diagnostic procedures.

While some individuals can defy the lure of temptation, many others find appetizing food irresistible. The goal of this study was to investigate the neuropsychological mechanisms that increase individuals' vulnerability to cue-induced eating. Using ERPs, a direct measure of brain activity, we showed that individuals with larger late positive potentials in response to food-related cues than to erotic images are more susceptible to cue-induced eating and, in the presence of a palatable food option, eat more than twice as much as individuals with the opposite brain reactivity profile. By highlighting the presence of individual brain reactivity profiles associated with susceptibility to cue-induced eating, these findings contribute to the understanding of the neurobiological basis of vulnerability to obesity.

There is accruing evidence of spontaneous dyskinesia in individuals with schizophrenia that is independent of medication exposure. Dyskinetic motor behavior is also present in individuals who are at high risk of schizophrenia and appears to have prognostic value for the development of psychosis. Nonetheless, it remains unclear whether dyskinesia is present in first-degree relatives of individuals with schizophrenia and thus associated with genetic liability for schizophrenia (i.e., an endophenotype), or whether the motor abnormality is a biomarker specific to the disease state spectrum. There is also limited information about links between dyskinesia and clinically relevant phenomena such as symptoms and cognition. Because dyskinesia marking genetic liability is likely to be subtle, we used sensitive instrument-based measurement of handwriting fluency to quantify dyskinesia in medicated individuals with schizophrenia or schizoaffective disorder, unaffected first-degree biological relatives of individuals with schizophrenia and schizoaffective disorder, and control participants. Results indicated that medicated individuals with schizophrenia or schizoaffective disorder exhibited more dyskinesia than both relatives and controls, with no difference between relatives and controls. Dyskinesia in individuals with schizophrenia or schizoaffective disorder was unrelated to current antipsychotic medication dosage, but associated with worse working memory function and greater positive formal thought disorder. These results provide evidence that dyskinesia is not associated with unexpressed genetic liability for schizophrenia.

PURPOSE: We investigated the neural correlates of emotion regulation and -reactivity in adult unaffected monozygotic twins with a co-twin history of unipolar or bipolar disorder (high-risk), remitted or partially remitted twins with a personal history of unipolar or bipolar disorder (affected) and twins with no personal or first-degree family history of unipolar or bipolar disorder (low-risk). METHODS: We assessed 37 high-risk, 56 affected and 28 low-risk participants. Participants viewed unpleasant and neutral pictures during functional magnetic resonance imaging and were instructed to down-regulate their emotional response through reappraisal or mental imagery, as well as to maintain the elicited emotion. RESULTS: After adjusting for subsyndromal depressive symptoms, bilateral supplementary motor areas, posterior dorsal anterior cingulate cortices and the left frontal eye field showed less activity during reappraisal of unpleasant pictures in high-risk than low-risk participants. Notably, affected participants did not differ from high-risk or low-risk participants in neural response during reappraisal. There were no group differences in ventrolateral prefrontal cortex seed based functional connectivity during reappraisal or neural response during mental imagery or emotional reactivity. CONCLUSION: Lesser response in dorsal midline areas might reflect familial risk related abnormalities during down regulation of emotional reactivity through reappraisal.

BackgroundClinical-pathological Alzheimer's disease (AD) subtypes may help distill heterogeneity in patient presentation. To date, no studies have utilized neuropsychological and biological markers to identify preclinical subtypes with longitudinal stability.ObjectiveThe objective of this study was to empirically derive AD endophenotypes using a combination of cognitive and biological markers.MethodsHierarchical cluster analysis grouped dementia-free older adults using memory, executive and language abilities, and cerebrospinal fluid amyloid-β and phosphorylated tau. Brain volume differences, neuropsychological trajectory, and progression to dementia were compared, controlling for age, gender, education, and apolipoprotein E4 (ApoE4).ResultsSubgroups included asymptomatic-normal (n = 653) with unimpaired cognition and subthreshold biomarkers, typical AD (TAD; n = 191) showing marked memory decline, high ApoE4 rates and abnormal biomarkers, and atypical AD (AAD; n = 132) with widespread cognitive decline, intermediate biomarker levels, older age, less education and more white matter lesions. Cognitive profiles showed longitudinal stability with corresponding patterns of cortical atrophy, despite nearly identical rates of progression to AD dementia.ConclusionTwo clinical-pathological AD subtypes are identified with potential implications for preventative efforts.

Genetic risk variants for schizophrenia have been linked to many related clinical and biological phenotypes with the hopes of delineating how individual variation across thousands of variants corresponds to the clinical and etiologic heterogeneity within schizophrenia. This has primarily been done using risk score profiling, which aggregates effects across all variants into a single predictor. While effective, this method lacks flexibility in certain domains: risk scores cannot capture nonlinear effects and do not employ any variable selection. We used random forest, an algorithm with this flexibility designed to maximize predictive power, to predict 6 cognitive endophenotypes in a combined sample of psychiatric patients and controls (N = 739) using 77 genetic variants strongly associated with schizophrenia. Tenfold cross-validation was applied to the discovery sample and models were externally validated in an independent sample of similar ancestry (N = 336). Linear approaches, including linear regression and task-specific polygenic risk scores, were employed for comparison. Random forest models for processing speed (P = .019) and visual memory (P = .036) and risk scores developed for verbal (P = .042) and working memory (P = .037) successfully generalized to an independent sample with similar predictive strength and error. As such, we suggest that both methods may be useful for mapping a limited set of predetermined, disease-associated SNPs to related phenotypes. Incorporating random forest and other more flexible algorithms into genotype-phenotype mapping inquiries could contribute to parsing heterogeneity within schizophrenia; such algorithms can perform as well as standard methods and can capture a more comprehensive set of potential relationships.

BackgroundThe Consortium on the Genetics of Schizophrenia (COGS) collected case-control endophenotype and genetic information from 2457 patients and healthy subjects (HS) across 5 test sites over 3.5 years. Analysis of the first "wave" (W1) of 1400 subjects identified prepulse inhibition (PPI) deficits in patients vs. HS. Data from the second COGS "wave" (W2), and the combined W(1+2), were used to assess: 1) the replicability of PPI deficits in this design; 2) the impact of response criteria on PPI deficits; and 3) PPI in a large cohort of antipsychotic-free patients.MethodsPPI in W2 HS (n=315) and schizophrenia patients (n=326) was compared to findings from W1; planned analyses assessed the impact of diagnosis, "wave" (1 vs. 2), and startle magnitude criteria. Combining waves allowed us to assess PPI in 120 antipsychotic-free patients, including many in the early course of illness.ResultsANOVA of all W(1+2) subjects revealed robust PPI deficits in patients across "waves" (p

Despite great interest in using magnetic resonance imaging (MRI) for studying the effects of genes on brain structure in humans, current approaches have focused almost entirely on predefined regions of interest and had limited success. Here, we used multivariate methods to define a single neuroanatomical score of how William's Syndrome (WS) brains deviate structurally from controls. The score is trained and validated on measures of T1 structural brain imaging in two WS cohorts (training, n = 38; validating, n = 60). We then associated this score with single nucleotide polymorphisms (SNPs) in the WS hemi-deleted region in five cohorts of neurologically and psychiatrically typical individuals (healthy European descendants, n = 1863). Among 110 SNPs within the 7q11.23 WS chromosomal region, we found one associated locus (p = 5e-5) located at GTF2IRD1, which has been implicated in animal models of WS. Furthermore, the genetic signals of neuroanatomical scores are highly enriched locally in the 7q11.23 compared with summary statistics based on regions of interest, such as hippocampal volumes (n = 12,596), and also globally (SNP-heritability = 0.82, se = 0.25, p = 5e-4). The role of genetic variability in GTF2IRD1 during neurodevelopment extends to healthy subjects. Our approach of learning MRI-derived phenotypes from clinical populations with well-established brain abnormalities characterized by known genetic lesions may be a powerful alternative to traditional region of interest-based studies for identifying genetic variants regulating typical brain development.

Impulsive personality traits are heritable risk factors and putative endophenotypes for addiction and other psychiatric disorders involving disinhibition. This study examined the genetic basis of impulsive personality traits, defined as scores on the Barratt Impulsiveness Scale (BIS-11) and the UPPS-P Impulsive Behavior Scale (UPPS-P). In 983 healthy young adults of European ancestry, the study examined genetic variation in relation to a combined phenotype of seven subscales based on high phenotypic intercorrelations. The study first tested 14 a priori loci that have previously been associated impulsive personality traits or closely related constructs. Second, the study included an exploratory genome-wide scan (i.e., GWAS), acknowledging that only relatively large effects would be detectable in a sample size of ~ 1000. A priori SNP analyses revealed a significant association between the combined impulsivity phenotype and two SNPs within the 5-HT2a receptor gene (HTR2A; rs6313 and rs6311). Follow-up analyses suggested that the effects were specific to the Motor and Non-planning subscales on the BIS-11, and also that the two loci were in linkage disequilibrium. The GWAS yielded no statistically significant findings. This study further implicates loci within HTR2A with certain forms of self-reported impulsivity and identifies candidates for future investigation from the genome-wide analyses.

ObjectiveHuman cognition has long been known to be under substantial genetic control. With the complete mapping of the human genome, genome-wide association studies for many complex traits have proliferated; however, the highly polygenic nature of intelligence has made the identification of the precise genes that influence both global and specific cognitive abilities more difficult than anticipated.MethodHere, we review the latest developments in the genomics of cognition, including a discussion of methodological advances in the genetic analysis of complex traits, and shared genetic contributions to cognitive abilities and neuropsychiatric disorders.ResultsA wealth of twin and family studies have provided compelling evidence for a strong heritable component of both global and specific cognitive abilities, and for the existence of "generalist genes" responsible for a large portion of the variance in diverse cognitive abilities. Increasingly sophisticated analytic tools and ever-larger sample sizes are now facilitating the identification of specific genetic and molecular underpinnings of cognitive abilities, leading to optimism regarding possibilities for novel treatments for illnesses related to cognitive function.ConclusionsWe conclude with a set of future directions for the field, which will further accelerate discoveries regarding the biological pathways relevant to cognitive abilities. These, in turn, may be further interrogated in order to link biological mechanisms to behavior. (PsycINFO Database Record

ObjectivePhenotypic heterogeneity in Tourette syndrome is partly due to complex genetic relationships among Tourette syndrome, obsessive-compulsive disorder (OCD), and attention deficit hyperactivity disorder (ADHD). Identifying symptom-based endophenotypes across diagnoses may aid gene-finding efforts.MethodAssessments for Tourette syndrome, OCD, and ADHD symptoms were conducted in a discovery sample of 3,494 individuals recruited for genetic studies. Symptom-level factor and latent class analyses were conducted in Tourette syndrome families and replicated in an independent sample of 882 individuals. Classes were characterized by comorbidity rates and proportion of parents included. Heritability and polygenic load associated with Tourette syndrome, OCD, and ADHD were estimated.ResultsThe authors identified two cross-disorder symptom-based phenotypes across analyses: symmetry (symmetry, evening up, checking obsessions; ordering, arranging, counting, writing-rewriting compulsions, repetitive writing tics) and disinhibition (uttering syllables/words, echolalia/palilalia, coprolalia/copropraxia, and obsessive urges to offend/mutilate/be destructive). Heritability estimates for both endophenotypes were high and statistically significant (disinhibition factor=0.35, SE=0.03; symmetry factor=0.39, SE=0.03; symmetry class=0.38, SE=0.10). Mothers of Tourette syndrome probands had high rates of symmetry (49%) but not disinhibition (5%). Polygenic risk scores derived from a Tourette syndrome genome-wide association study (GWAS) were significantly associated with symmetry, while risk scores derived from an OCD GWAS were not. OCD polygenic risk scores were significantly associated with disinhibition, while Tourette syndrome and ADHD risk scores were not.ConclusionsThe analyses identified two heritable endophenotypes related to Tourette syndrome that cross traditional diagnostic boundaries. The symmetry phenotype correlated with Tourette syndrome polygenic load and was present in otherwise Tourette-unaffected mothers, suggesting that this phenotype may reflect additional Tourette syndrome (rather than OCD) genetic liability that is not captured by traditional DSM-based diagnoses.

BackgroundAutism spectrum disorder (ASD) is characterized by social communication deficits and restricted, repetitive patterns of behavior. Varied immunological findings have been reported in children with ASD. To address the question of heterogeneity in immune responses, we sought to examine the diversity of immune profiles within a representative cohort of boys with ASD.MethodsPeripheral blood mononuclear cells from male children with ASD (n = 50) and from typically developing age-matched male control subjects (n = 16) were stimulated with either lipopolysaccharide or phytohemagglutinin. Cytokine production was assessed after stimulation. The ASD study population was clustered into subgroups based on immune responses and assessed for behavioral outcomes.ResultsChildren with ASD who had a proinflammatory profile based on lipopolysaccharide stimulation were more developmentally impaired as assessed by the Mullen Scales of Early Learning. They also had greater impairments in social affect as measured by the Autism Diagnostic Observation Schedule. These children also displayed more frequent sleep disturbances and episodes of aggression. Similarly, children with ASD and a more activated T cell cytokine profile after phytohemagglutinin stimulation were more developmentally impaired as measured by the Mullen Scales of Early Learning.ConclusionsChildren with ASD may be phenotypically characterized based upon their immune profile. Those showing either an innate proinflammatory response or increased T cell activation/skewing display a more impaired behavioral profile than children with noninflamed or non-T cell activated immune profiles. These data suggest that there may be several possible immune subphenotypes within the ASD population that correlate with more severe behavioral impairments.

ObjectiveTo identify genetic loci associated with plasma tau concentrations in healthy elders and individuals with Alzheimer disease.MethodsFour hundred sixty-three non-Hispanic white individuals exceeding quality control criteria were included from the Alzheimer's Disease Neuroimaging Initiative (ADNI-1) cohort. Association of plasma tau with genetic polymorphisms was performed with a linear regression model. Significant associations were validated in an independent replication cohort consisting of 431 healthy elders or individuals with mild cognitive impairment recruited from the University of California, San Francisco Memory and Aging Center.ResultsThe minor allele (A) of rs242557 in the microtubule-associated protein tau gene (MAPT) was associated with higher plasma tau levels at genome-wide significance (p = 4.85 × 10-9, empiric family-wise error corrected p = 0.0024) in a dose-dependent fashion. This association was also observed in the replication cohort (p = 1.0 × 10-5; joint analysis p = 1.2 × 10-12). Single nucleotide polymorphisms near PARK2 (rs2187213) (p = 6.15 × 10-6), IL2RA (rs7072793, rs7073236) (p = 7.89 × 10-6), and an intergenic locus on 9p21.3 (rs7047280) (p = 8.13 × 10-6) were identified as suggestive loci associated with plasma tau levels.ConclusionsMAPT H1c haplotype (rs242557) has previously been identified as a genetic risk factor for progressive supranuclear palsy and corticobasal degeneration. The current findings suggest that plasma tau concentration could be an endophenotype for identifying risk for 4-repeat tauopathies in older individuals.

First, we describe the hallmark contributions of Irv Gottesman's pioneering scholarship for schizophrenia research including concepts of polygenicity, gene × environment interactions, epigenetics and the endophenotype concept. Gottesman and colleagues' twin studies showed that genes, not social factors, mediate schizophrenia risk. He then showed that schizophrenia is highly polygenic. Next, he introduced the concept of epigenetics into schizophrenia research. Gottesman then introduced the quantitative endophenotype concept. Endophenotypes are laboratory-based measures that show deficits in schizophrenia patients and lesser deficits in their first degree "unaffected" relatives and are viewed as being more proximal to genes and having a simpler genetic architecture than are "fuzzy" qualitative diagnostic disorders. Endophenotypes offer an exciting path to gene discovery, neural circuits, genetic architecture and new treatment pathways of schizophrenia and related psychotic disorders. Second, we were asked to discuss 2 of many endophenotype Consortia and related studies, in order to illustrate the impact of Gottesman's work. We describe the Consortium on the Genetics of Schizophrenia (COGS) exploring neurocognitive and neurophysiological endophenotypes in family and case-control studies. Association, linkage, sequencing and epigenetic studies are described. The Bipolar and Schizophrenia Network for Intermediate Phenotypes (BSNIP) uses an array of endophenotypes including brain imaging in studies across the psychosis dimension, allowing for dimensional analyses. BSNIP results have led to the concept of biotypes, advancing the field. Irv Gottesman was imaginatively prescient in generating novel insights and predicting many major issues which challenge schizophrenia researchers who still use his concepts to guide current research approaches.

The blood-brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 × 10-8, β=0.08) and DDX6 (P=2.9 × 10-7, β=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 × 10-52). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain-expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset neurodegenerative disorder, characterized by tremors, ataxia, impaired coordination, and cognitive decline. While all FXTAS individuals are carriers of a 55-200 CGG expansion at the 5'-UTR of the fragile X mental retardation gene (FMR1), also known as premutation, not all carriers develop FXTAS symptoms and some display other types of psychological/emotional disorders (e.g., autism, anxiety). The goal of this study was to investigate whether the mitochondrial dysfunction previously observed in fibroblasts from older premutation individuals (>60 years) was already present in younger (17-48 years), non-FXTAS-affected carriers and to identify the type and severity of the bioenergetic deficit. Since FXTAS affects mostly males, while females account for a small part of the FXTAS-affected population displaying less severe symptoms, only fibroblasts from males were evaluated in this study. Based on polarographic and enzymatic measurements, a generalized OXPHOS deficit was noted accompanied by increases in the matrix biomarker citrate synthase, oxidative stress (as increased mtDNA copy number and deletions), and mitochondrial network disruption/disorganization. Some of the outcomes (ATP-linked oxygen uptake, coupling, citrate synthase activity, and mitochondrial network organization) strongly correlated with the extent of the CGG expansion, with more severe deficits observed in cell lines carrying higher CGG number. Furthermore, mitochondrial outcomes can identify endophenotypes among carriers and are robust predictors of the premutation diagnosis before the onset of FXTAS, with the potential to be used as markers of prognosis and/or as readouts of pharmacological interventions.

Past studies describe numerous endophenotypes associated with schizophrenia (SZ), but many endophenotypes may overlap in information they provide, and few studies have investigated the utility of a multivariate index to improve discrimination between SZ and healthy community comparison subjects (CCS). We investigated 16 endophenotypes from the first phase of the Consortium on the Genetics of Schizophrenia, a large, multi-site family study, to determine whether a subset could distinguish SZ probands and CCS just as well as using all 16. Participants included 345 SZ probands and 517 CCS with a valid measure for at least one endophenotype. We used both logistic regression and random forest models to choose a subset of endophenotypes, adjusting for age, gender, smoking status, site, parent education, and the reading subtest of the Wide Range Achievement Test. As a sensitivity analysis, we re-fit models using multiple imputations to determine the effect of missing values. We identified four important endophenotypes: antisaccade, Continuous Performance Test-Identical Pairs 3-digit version, California Verbal Learning Test, and emotion identification. The logistic regression model that used just these four endophenotypes produced essentially the same results as the model that used all 16 (84% vs. 85% accuracy). While a subset of endophenotypes cannot replace clinical diagnosis nor encompass the complexity of the disease, it can aid in the design of future endophenotypic and genetic studies by reducing study cost and subject burden, simplifying sample enrichment, and improving the statistical power of locating those genetic regions associated with schizophrenia that may be the easiest to identify initially.

BackgroundImpulsivity is associated with bipolar disorder as a clinical feature during and between manic episodes and is considered a potential endophenotype for the disorder. Schizophrenia and major depressive disorder share substantial genetic overlap with bipolar disorder, and these two disorders have also been associated with elevations in impulsivity. However, little is known about the degree of overlap among these disorders in discrete subfacets of impulsivity and whether any overlap is purely phenotypic or due to shared genetic diathesis.MethodWe focused on five subfacets of impulsivity: self-reported attentional, motor, and non-planning impulsivity, self-reported sensation seeking, and a behavioral measure of motor inhibition (stop signal reaction time; SSRT). We examined these facets within and across disorder proband and co-twin groups, modeled heritability, and tested for endophenotypic patterning in a sample of twin pairs recruited from the Swedish Twin Registry (N = 420).ResultsWe found evidence of moderate to high levels of heritability for all five subfacets. All three proband groups and their unaffected co-twins showed elevations on attentional, motor, and non-planning impulsivity. Schizophrenia probands (but not their co-twins) showed significantly lower sensation seeking, and schizophrenia and bipolar disorder probands (but not in their co-twins) had significantly longer SSRTs, compared with healthy controls and the other groups.ConclusionsAttentional, motor, and non-planning impulsivity emerged as potential shared endophenotypes for the three disorders, whereas sensation seeking and SSRT were associated with phenotypic affection but not genetic loading for these disorders.

ObjectiveThe Consortium on the Genetics of Schizophrenia Family Study evaluated 12 primary and other supplementary neurocognitive and neurophysiological endophenotypes in schizophrenia probands and their families. Previous analyses of prepulse inhibition (PPI) and P50 gating measures in this sample revealed heritability estimates that were lower than expected based on earlier family studies. Here the authors investigated whether gating measures were more heritable in multiply affected families with a positive family history compared with families with only a single affected proband (singleton).MethodA total of 296 nuclear families consisting of a schizophrenia proband, at least one unaffected sibling, and both parents underwent a comprehensive endophenotype and clinical characterization. The Family Interview for Genetic Studies was administered to all participants and used to obtain convergent psychiatric symptom information for additional first-degree relatives. Among the families, 97 were multiply affected, and 96 were singletons.ResultsBoth PPI and P50 gating displayed substantially increased heritability in the 97 multiply affected families (47% and 36%, respectively) compared with estimates derived from the entire sample of 296 families (29% and 20%, respectively). However, no evidence for heritability was observed for either measure in the 96 singleton families. Schizophrenia probands derived from the multiply affected families also displayed a significantly increased severity of clinical symptoms compared with those from singleton families.ConclusionsPPI and P50 gating measures demonstrate substantially increased heritability in schizophrenia families with a higher genetic vulnerability for illness, providing further support for the commonality of genes underlying both schizophrenia and gating measures.

Endophenotypes are quantitative, heritable traits that may help to elucidate the pathophysiologic mechanisms underlying complex disease syndromes, such as schizophrenia. They can be assessed at numerous levels of analysis; here, we review electrophysiological endophenotypes that have shown promise in helping us understand schizophrenia from a more mechanistic point of view. For each endophenotype, we describe typical experimental procedures, reliability, heritability, and reported gene and neurobiological associations. We discuss recent findings regarding the genetic architecture of specific electrophysiological endophenotypes, as well as converging evidence from EEG studies implicating disrupted balance of glutamatergic signaling and GABAergic inhibition in the pathophysiology of schizophrenia. We conclude that refining the measurement of electrophysiological endophenotypes, expanding genetic association studies, and integrating data sets are important next steps for understanding the mechanisms that connect identified genetic risk loci for schizophrenia to the disease phenotype.

The immune response is highly active in Alzheimer's disease (AD). Identification of genetic risk contributed by immune genes to AD may provide essential insight for the prognosis, diagnosis, and treatment of this neurodegenerative disease. In this study, we performed a genetic screening for AD-related top immune genes identified in Europeans in a Chinese cohort, followed by a multiple-stage study focusing on Complement Factor H (CFH) gene. Effects of the risk SNPs on AD-related neuroimaging endophenotypes were evaluated through magnetic resonance imaging scan, and the effects on AD cerebrospinal fluid biomarkers (CSF) and CFH expression changes were measured in aged and AD brain tissues and AD cellular models. Our results showed that the AD-associated top immune genes reported in Europeans (CR1, CD33, CLU, and TREML2) have weak effects in Chinese, whereas CFH showed strong effects. In particular, rs1061170 (P(meta)=5.0 × 10(-4)) and rs800292 (P(meta)=1.3 × 10(-5)) showed robust associations with AD, which were confirmed in multiple world-wide sample sets (4317 cases and 16 795 controls). Rs1061170 (P=2.5 × 10(-3)) and rs800292 (P=4.7 × 10(-4)) risk-allele carriers have an increased entorhinal thickness in their young age and a higher atrophy rate as the disease progresses. Rs800292 risk-allele carriers have higher CSF tau and Aβ levels and severe cognitive decline. CFH expression level, which was affected by the risk-alleles, was increased in AD brains and cellular models. These comprehensive analyses suggested that CFH is an important immune factor in AD and affects multiple pathological changes in early life and during disease progress.

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.

Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes.

Genome-wide association studies have associated clusterin (CLU) variants with Alzheimer's disease (AD). However, the role of CLU on AD pathogenesis is not totally understood. We used cerebrospinal fluid (CSF) and plasma CLU levels as endophenotypes for genetic studies to understand the role of CLU in AD. CSF, but not plasma, CLU levels were significantly associated with AD status and CSF tau/amyloid-beta ratio, and highly correlated with CSF apolipoprotein E (APOE) levels. Several loci showed almost genome-wide significant associations including LINC00917 (p = 3.98 × 10(-7)) and interleukin 6 (IL6, p = 9.94 × 10(-6), in the entire data set and in the APOE ε4- individuals p = 7.40 × 10(-8)). Gene ontology analyses suggest that CSF CLU levels may be associated with wound healing and immune response which supports previous functional studies that demonstrated an association between CLU and IL6. CLU may play a role in AD by influencing immune system changes that have been observed in AD or by disrupting healing after neurodegeneration.

The Consortium on the Genetics of Schizophrenia Family Study (COGS-1) has previously reported our efforts to characterize the genetic architecture of 12 primary endophenotypes for schizophrenia. We now report the characterization of 13 additional measures derived from the same endophenotype test paradigms in the COGS-1 families. Nine of the measures were found to discriminate between schizophrenia patients and controls, were significantly heritable (31 to 62%), and were sufficiently independent of previously assessed endophenotypes, demonstrating utility as additional endophenotypes. Genotyping via a custom array of 1536 SNPs from 94 candidate genes identified associations for CTNNA2, ERBB4, GRID1, GRID2, GRIK3, GRIK4, GRIN2B, NOS1AP, NRG1, and RELN across multiple endophenotypes. An experiment-wide p value of 0.003 suggested that the associations across all SNPs and endophenotypes collectively exceeded chance. Linkage analyses performed using a genome-wide SNP array further identified significant or suggestive linkage for six of the candidate endophenotypes, with several genes of interest located beneath the linkage peaks (e.g., CSMD1, DISC1, DLGAP2, GRIK2, GRIN3A, and SLC6A3). While the partial convergence of the association and linkage likely reflects differences in density of gene coverage provided by the distinct genotyping platforms, it is also likely an indication of the differential contribution of rare and common variants for some genes and methodological differences in detection ability. Still, many of the genes implicated by COGS through endophenotypes have been identified by independent studies of common, rare, and de novo variation in schizophrenia, all converging on a functional genetic network related to glutamatergic neurotransmission that warrants further investigation.

A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice.

Bipolar disorder is a complex neuropsychiatric disorder that is characterized by intermittent episodes of mania and depression; without treatment, 15% of patients commit suicide. Hence, it has been ranked by the World Health Organization as a top disorder of morbidity and lost productivity. Previous neuropathological studies have revealed a series of alterations in the brains of patients with bipolar disorder or animal models, such as reduced glial cell number in the prefrontal cortex of patients, upregulated activities of the protein kinase A and C pathways and changes in neurotransmission. However, the roles and causation of these changes in bipolar disorder have been too complex to exactly determine the pathology of the disease. Furthermore, although some patients show remarkable improvement with lithium treatment for yet unknown reasons, others are refractory to lithium treatment. Therefore, developing an accurate and powerful biological model for bipolar disorder has been a challenge. The introduction of induced pluripotent stem-cell (iPSC) technology has provided a new approach. Here we have developed an iPSC model for human bipolar disorder and investigated the cellular phenotypes of hippocampal dentate gyrus-like neurons derived from iPSCs of patients with bipolar disorder. Guided by RNA sequencing expression profiling, we have detected mitochondrial abnormalities in young neurons from patients with bipolar disorder by using mitochondrial assays; in addition, using both patch-clamp recording and somatic Ca(2+) imaging, we have observed hyperactive action-potential firing. This hyperexcitability phenotype of young neurons in bipolar disorder was selectively reversed by lithium treatment only in neurons derived from patients who also responded to lithium treatment. Therefore, hyperexcitability is one early endophenotype of bipolar disorder, and our model of iPSCs in this disease might be useful in developing new therapies and drugs aimed at its clinical treatment.

BackgroundWeak central coherence-a tendency to process details at the expense of the gestalt-has been observed among adults with bulimia nervosa (BN) and is a potential candidate endophenotype for eating disorders (EDs). However, as BN behaviors typically onset during adolescence it is important to assess central coherence in this younger age group to determine whether the findings in adults are likely a result of BN or present earlier in the evolution of the disorder. This study examines whether the detail-oriented and fragmented cognitive inefficiency observed among adults with BN is observable among adolescents with shorter illness duration, relative to healthy controls.MethodThe Rey-Osterrieth Complex Figure Test (RCFT) was administered to a total of 47 adolescents with DSM5 BN, 42 with purging disorder (PD), and 25 healthy controls (HC). Performance on this measure was compared across the three groups.ResultsThose with BN and PD demonstrated significantly worse accuracy scores compared to controls in the copy and delayed recall condition with a moderate effect size. These findings were exacerbated when symptoms of BN increased.DiscussionPoorer accuracy scores reflect a fragmented and piecemeal strategy that interferes with visual-spatial integration in BN spectrum disorders. This cognitive inefficiency likely contributes to broad difficulties in executive functioning in this population especially in the context of worsening bulimic symptoms. The findings of this study support the hypothesis that poor global integration may constitute a cognitive endophenotype for BN.

Symptoms of autism are frequent in males with fragile X syndrome (FXS), but it is not clear whether symptom profiles differ from those of nonsyndromic ASD. Using individual item scores from the Autism Diagnostic Inventory-Revised, we examined which current symptoms of autism differed in boys with FXS relative to same-aged boys diagnosed with nonsyndromic ASD. In addition, different subsamples of participants were matched on autism diagnostic status and severity of autism symptoms. Between-group comparisons revealed that boys with FXS showed significantly less impairment in Social Smiling than did age-, diagnostic-, and severity-matched boys with nonsyndromic ASD. Severity-matched boys with FXS showed more impairment in complex mannerisms than did boys with nonsyndromic ASD. Behavioral differences between FXS and nonsyndromic ASD may be of theoretical importance in understanding the causes and correlates of ASD in FXS and in developing and implementing appropriate treatments.

Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity.

Attention/vigilance impairments are present in individuals with schizophrenia across psychotic and remitted states and in their first-degree relatives. An important question is whether deficits in attention/vigilance can be consistently and reliably measured across sites varying in many participant demographic, clinical, and functional characteristics, as needed for large-scale genetic studies of endophenotypes. We examined Continuous Performance Test (CPT) data from phase 2 of the Consortium on the Genetics of Schizophrenia (COGS-2), the largest-scale assessment of cognitive and psychophysiological endophenotypes relevant to schizophrenia. The CPT data from 2251 participants from five sites were examined. A perceptual-load vigilance task (the Degraded Stimulus CPT or DS-CPT) and a memory-load vigilance task (CPT-Identical Pairs or CPT-IP) were utilized. Schizophrenia patients performed more poorly than healthy comparison subjects (HCS) across sites, despite significant site differences in participant age, sex, education, and racial distribution. Patient-HCS differences in signal/noise discrimination (d') in the DS-CPT varied significantly across sites, but averaged a medium effect size. CPT-IP performance showed large patient-HCS differences across sites. Poor CPT performance was independent of or weakly correlated with symptom severity, but was significantly associated with lower educational achievement and functional capacity. Current smoking was associated with poorer CPT-IP d'. Patients taking both atypical and typical antipsychotic medication performed more poorly than those on no or atypical antipsychotic medications, likely reflecting their greater severity of illness. We conclude that CPT deficits in schizophrenia can be reliably detected across sites, are relatively independent of current symptom severity, and are related to functional capacity.

BackgroundThe COGS is a multi-site NIMH-sponsored investigation of the genetic basis of 12 primary and multiple secondary quantitative endophenotypes in schizophrenia.MethodsSince 2003, COGS has completed studies using a family-based ascertainment strategy (COGS-1), and a case-control ascertainment strategy (COGS-2) (cumulative "n">4000).ResultsCOGS-1 family study confirmed robust deficits in, and heritability of, these endophenotypes in schizophrenia, and provided evidence for a coherent genetic architecture underlying the risk for neurocognitive and neurophysiological deficits in this disorder. COGS-2 case-control findings, many reported herein, establish a foundation for fine genomic mapping and other analyses of these endophenotypes and risk genes for SZ. Several reports in this Special Issue compare findings of endophenotype deficits generated by fundamentally different COGS-1 vs. COGS-2 ascertainment strategies. Despite the expectation that family-based and case-control designs would establish demographically and potentially biologically distinct patient cohorts, findings generally revealed comparable patterns of endophenotype deficits across studies. The COGS-2 case-control design facilitated the accrual of a larger "n", permitting detailed analyses of factors moderating endophenotype performance. Some COGS-2 endophenotypes not assessed in COGS-1 are also reported, as is a new factor analytic strategy for identifying shared vs. unique factors among the COGS endophenotypes which can be used to develop composite variables with distinct genetic signatures.DiscussionThe path to date of COGS-1 endophenotype and genetic findings, followed by replication and extension in COGS-2, establishes benchmarks for endophenotype deficits in SZ and their moderation by specific factors, and clear expectations for informative findings from upcoming COGS-2 genetic analyses.

There are varying, often conflicting, reports with respect to altered striatal volume and morphometry in the major psychoses due to the influences of antipsychotic medications on striatal volume. Thus, disassociating disease effects from those of medication become exceedingly difficult. For the first time, using a longitudinally studied sample of structural magnetic resonance images from patients with childhood onset schizophrenia (COS; neurobiologically contiguous with the adult onset form of schizophrenia), their nonpsychotic siblings (COSSIBs), and novel shape mapping algorithms that are volume independent, we report the familial contribution of striatal morphology in schizophrenia. The results of our volumetric analyses demonstrate age-related increases in overall striatal volumes specific only to COS. However, both COS and COSSIBs showed overlapping shape differences in the striatal head, which normalized in COSSIBs by late adolescence. These results mirror previous studies from our group, demonstrating cortical thickness deficits in COS and COSSIBs as these deficits normalize in COSSIBs in the same age range as our striatal findings. Finally, there is a single region of nonoverlapping outward displacement in the dorsal aspect of the caudate body, potentially indicative of a response to medication. Striatal shape may be considered complimentary to volume as an endophenotype, and, in some cases may provide information that is not detectable using standard volumetric techniques. Our striatal shape findings demonstrate the striking localization of abnormalities in striatal the head. The neuroanatomical localization of these findings suggest the presence of abnormalities in the striatal-prefrontal circuits in schizophrenia and resilience mechanisms in COSSIBs with age dependent normalization.

The first phase of the Consortium on the Genetics of Schizophrenia (COGS-1) showed performance deficits in learning and memory on the California Verbal Learning Test, Second Edition (CVLT-II) in individuals with schizophrenia (SZ), compared to healthy comparison subjects (HCS). A question is whether the COGS-1 study, which used a family study design (i.e. studying relatively intact families), yielded "milder" SZ phenotypes than those acquired subsequently in the COGS-2 case-control design that did not recruit unaffected family members. CVLT-II performance was compared for the COGS-1 and COGS-2 samples. Analyses focused on learning, recall and recognition variables, with age, gender and education as covariates. Analyses of COGS-2 data explored effects of additional covariates and moderating factors in CVLT-II performance. 324 SZ subjects and 510 HCS had complete CVLT-II and covariate data in COGS-1, while 1356 SZ and 1036 HCS had complete data in COGS-2. Except for recognition memory, analysis of covariance showed significantly worse performance in COGS-2 on all CVLT-II variables for SZ and HCS, and remained significant in the presence of the covariates. Performance in each of the 5 learning trials differed significantly. However, effect sizes comparing cases and controls were comparable across the two studies. COGS-2 analyses confirmed SZ performance deficits despite effects of multiple significant covariates and moderating factors. CVLT-II performance was worse in COGS-2 than in COGS-1 for both the SZ and the HCS in this large cohort, likely due to cohort effects. Demographically corrected data yield a consistent pattern of performance across the two studies in SZ.

The impaired ability to make correct antisaccades (i.e., antisaccade performance) is well documented among schizophrenia subjects, and researchers have successfully demonstrated that antisaccade performance is a valid schizophrenia endophenotype that is useful for genetic studies. However, it is unclear how the ascertainment biases that unavoidably result from recruitment differences in schizophrenia subjects identified in family versus case-control studies may influence patient-control differences in antisaccade performance. To assess the impact of ascertainment bias, researchers from the Consortium on the Genetics of Schizophrenia (COGS) compared antisaccade performance and antisaccade metrics (latency and gain) in schizophrenia and control subjects from COGS-1, a family-based schizophrenia study, to schizophrenia and control subjects from COGS-2, a corresponding case-control study. COGS-2 schizophrenia subjects were substantially older; had lower education status, worse psychosocial function, and more severe symptoms; and were three times more likely to be a member of a multiplex family than COGS-1 schizophrenia subjects. Despite these variations, which were likely the result of ascertainment differences (as described in the introduction to this special issue), the effect sizes of the control-schizophrenia differences in antisaccade performance were similar in both studies (Cohen's d effect size of 1.06 and 1.01 in COGS-1 and COGS-2, respectively). This suggests that, in addition to the robust, state-independent schizophrenia-related deficits described in endophenotype studies, group differences in antisaccade performance do not vary based on subject ascertainment and recruitment factors.

ObjectivesWorking memory impairment has been extensively studied in schizophrenia, but less is known about moderators of the impairment. Using the Consortium on the Genetics of Schizophrenia case-control study (COGS-2), we examined smoking status, types of antipsychotic medication, and history of substance as moderators for working memory impairment in schizophrenia.MethodsFrom 5 sites, 1377 patients with schizophrenia or schizoaffective, depressed type and 1037 healthy controls completed the letter-number span (LNS) task. The LNS uses intermixed letter and digit stimuli that increase from 2 up to 8 stimuli. In the forward condition, participants repeated the letters and numbers in the order they were presented. In the reorder condition, participants repeated the digits in ascending order followed by letters in alphabetical order.ResultsSchizophrenia patients performed more poorly than controls, with a larger difference on reorder than forward conditions. Deficits were associated with symptoms, functional capacity, and functional outcome. Patients who smoked showed larger impairment than nonsmoking patients, primarily due to deficits on the reorder condition. The impairing association of smoking was more pronounced among patients taking first-generation than those taking second-generation antipsychotic medications. Correlations between working memory and community functioning were stronger for nonsmokers. History of substance use did not moderate working memory impairment.ConclusionsResults confirm the working memory impairment in schizophrenia, and indicate smoking status as an important moderator for these deficits. The greater impairment in smokers may reflect added burden of smoking on general health or that patients with greater deficits are more likely to smoke.