GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

The complex nature of human cognition has resulted in cognitive genomics lagging behind many other fields in terms of gene discovery using genome-wide association study (GWAS) methods. In an attempt to overcome these barriers, the current study utilized GWAS meta-analysis to examine the association of common genetic variation (~8M single-nucleotide polymorphisms (SNP) with minor allele frequency ⩾1%) to general cognitive function in a sample of 35 298 healthy individuals of European ancestry across 24 cohorts in the Cognitive Genomics Consortium (COGENT). In addition, we utilized individual SNP lookups and polygenic score analyses to identify genetic overlap with other relevant neurobehavioral phenotypes. Our primary GWAS meta-analysis identified two novel SNP loci (top SNPs: rs76114856 in the CENPO gene on chromosome 2 and rs6669072 near LOC105378853 on chromosome 1) associated with cognitive performance at the genome-wide significance level (P<5 × 10-8). Gene-based analysis identified an additional three Bonferroni-corrected significant loci at chromosomes 17q21.31, 17p13.1 and 1p13.3. Altogether, common variation across the genome resulted in a conservatively estimated SNP heritability of 21.5% (s.e.=0.01%) for general cognitive function. Integration with prior GWAS of cognitive performance and educational attainment yielded several additional significant loci. Finally, we found robust polygenic correlations between cognitive performance and educational attainment, several psychiatric disorders, birth length/weight and smoking behavior, as well as a novel genetic association to the personality trait of openness. These data provide new insight into the genetics of neurocognitive function with relevance to understanding the pathophysiology of neuropsychiatric illness.

GWAS meta-analysis reveals novel loci and genetic correlates for general cognitive function: a report from the COGENT consortium.

This corrects the article DOI: 10.1038/mp.2016.244.

Genome-wide autozygosity is associated with lower general cognitive ability.

Inbreeding depression refers to lower fitness among offspring of genetic relatives. This reduced fitness is caused by the inheritance of two identical chromosomal segments (autozygosity) across the genome, which may expose the effects of (partially) recessive deleterious mutations. Even among outbred populations, autozygosity can occur to varying degrees due to cryptic relatedness between parents. Using dense genome-wide single-nucleotide polymorphism (SNP) data, we examined the degree to which autozygosity associated with measured cognitive ability in an unselected sample of 4854 participants of European ancestry. We used runs of homozygosity-multiple homozygous SNPs in a row-to estimate autozygous tracts across the genome. We found that increased levels of autozygosity predicted lower general cognitive ability, and estimate a drop of 0.6 s.d. among the offspring of first cousins (P=0.003-0.02 depending on the model). This effect came predominantly from long and rare autozygous tracts, which theory predicts as more likely to be deleterious than short and common tracts. Association mapping of autozygous tracts did not reveal any specific regions that were predictive beyond chance after correcting for multiple testing genome wide. The observed effect size is consistent with studies of cognitive decline among offspring of known consanguineous relationships. These findings suggest a role for multiple recessive or partially recessive alleles in general cognitive ability, and that alleles decreasing general cognitive ability have been selected against over evolutionary time.

Modelling difficulties in abstract thinking in psychosis: the importance of socio-developmental background.

INTRODUCTION: Abstract thinking is important in modern understanding of neurocognitive abilities, and a symptom of thought disorder in psychosis. In patients with psychosis, we assessed if socio-developmental background influences abstract thinking, and the association with executive functioning and clinical psychosis symptoms. METHODS: Participants (n = 174) had a diagnosis of psychotic or bipolar disorder, were 17-65 years, intelligence quotient (IQ) > 70, fluent in a Scandinavian language, and their full primary education in Norway. Immigrants (N = 58) were matched (1:2) with participants without a history of migration (N = 116). All participants completed a neurocognitive and clinical assessment. Socio-developmental background was operationalised as human developmental index (HDI) of country of birth, at year of birth. Structural equation modelling was used to assess the model with best fit. RESULTS: The model with best fit, χ2 = 96.591, df = 33, p < .001, confirmed a significant indirect effect of HDI scores on abstract thinking through executive functioning, but not through clinical psychosis symptoms. CONCLUSIONS: This study found that socio-developmental background influences abstract thinking in psychosis by indirect effect through executive functioning. We should take into account socio-developmental background in the interpretation of neurocognitive performance in patients with psychosis, and prioritise cognitive remediation in treatment of immigrant patients.

Molecular genetic evidence for overlap between general cognitive ability and risk for schizophrenia: a report from the Cognitive Genomics consorTium (COGENT).

It has long been recognized that generalized deficits in cognitive ability represent a core component of schizophrenia (SCZ), evident before full illness onset and independent of medication. The possibility of genetic overlap between risk for SCZ and cognitive phenotypes has been suggested by the presence of cognitive deficits in first-degree relatives of patients with SCZ; however, until recently, molecular genetic approaches to test this overlap have been lacking. Within the last few years, large-scale genome-wide association studies (GWAS) of SCZ have demonstrated that a substantial proportion of the heritability of the disorder is explained by a polygenic component consisting of many common single-nucleotide polymorphisms (SNPs) of extremely small effect. Similar results have been reported in GWAS of general cognitive ability. The primary aim of the present study is to provide the first molecular genetic test of the classic endophenotype hypothesis, which states that alleles associated with reduced cognitive ability should also serve to increase risk for SCZ. We tested the endophenotype hypothesis by applying polygenic SNP scores derived from a large-scale cognitive GWAS meta-analysis (~5000 individuals from nine nonclinical cohorts comprising the Cognitive Genomics consorTium (COGENT)) to four SCZ case-control cohorts. As predicted, cases had significantly lower cognitive polygenic scores compared to controls. In parallel, polygenic risk scores for SCZ were associated with lower general cognitive ability. In addition, using our large cognitive meta-analytic data set, we identified nominally significant cognitive associations for several SNPs that have previously been robustly associated with SCZ susceptibility. Results provide molecular confirmation of the genetic overlap between SCZ and general cognitive ability, and may provide additional insight into pathophysiology of the disorder.

Schizophrenia patients with and without post-traumatic stress disorder (PTSD) have different mood symptom levels but same cognitive functioning.

OBJECTIVE: To investigate differences in cognitive function and level of psychopathology in patients with schizophrenia (SZ) with or without psychological traumatization/post-traumatic stress disorder (PTSD). We hypothesized that traumatized patients with or without PTSD would have more severe cognitive impairments because of the neuropathological changes associated with PTSD, and more severe psychopathology compared with non-traumatized SZ patients. METHOD: Seventy-five SZ patients with traumatization and 217 SZ patients without traumatization were evaluated regarding the symptoms and cognitive functioning, using standard symptom scales (PANSS; CDSS) and a neuropsychological test battery (IQ, verbal memory, attention, working memory, psychomotor speed, and executive functioning). RESULTS: No significant differences were observed between the groups in cognitive test performance. The patients in the traumatized group with PTSD showed significantly more current depression than the non-traumatized group (P = 0.012). CONCLUSION: The findings did not support the hypothesis that the presence of comorbid PTSD/traumatization in SZ is associated with increased cognitive impairment. The increase in current depression in SZ with comorbid traumatization suggests that more severe psychopathology is associated with traumatization.

Predictors of medication adherence in patients with schizophrenia and bipolar disorder.

OBJECTIVE: To investigate potential risk factors for medication non-adherence in patients with schizophrenia and bipolar disorder. METHOD: A total of 255 patients underwent clinical assessments, neurocognitive testing and blood sampling. The patients were divided into groups of 'No', 'Partial' or 'Full' adherence. Relationships to different risk factors were analyzed. RESULTS: In schizophrenia, use of illicit substances, alcohol and poor insight were related to worse adherence. Schizophrenia patients with No adherence did better on tests of executive functioning, verbal learning and memory and had higher IQ than patients with better adherence. There were higher levels of autonomic side effects in the non-adherence group, but body mass index was lower in the Partial adherence group than in the Full adherence group. In the bipolar disorder patients, there was an association between the use of illicit substances and alcohol and poor adherence. We found no relationship between adherence behavior and neurocognition in the bipolar disorder group. CONCLUSION: Substance use is an important risk factor for non-adherence in patients with schizophrenia and bipolar disorder. Poor insight is also a risk factor in schizophrenia. The results suggest that cognitive dysfunction is not a risk factor for non-adherence in these diagnostic groups.

Neuropsychological testing of cognitive impairment in euthymic bipolar disorder: an individual patient data meta-analysis.

OBJECTIVE: An association between bipolar disorder and cognitive impairment has repeatedly been described, even for euthymic patients. Findings are inconsistent both across primary studies and previous meta-analyses. This study reanalysed 31 primary data sets as a single large sample (N = 2876) to provide a more definitive view. METHOD: Individual patient and control data were obtained from original authors for 11 measures from four common neuropsychological tests: California or Rey Verbal Learning Task (VLT), Trail Making Test (TMT), Digit Span and/or Wisconsin Card Sorting Task. RESULTS: Impairments were found for all 11 test-measures in the bipolar group after controlling for age, IQ and gender (Ps ≤ 0.001, E.S. = 0.26-0.63). Residual mood symptoms confound this result but cannot account for the effect sizes found. Impairments also seem unrelated to drug treatment. Some test-measures were weakly correlated with illness severity measures suggesting that some impairments may track illness progression. CONCLUSION: This reanalysis supports VLT, Digit Span and TMT as robust measures of cognitive impairments in bipolar disorder patients. The heterogeneity of some test results explains previous differences in meta-analyses. Better controlling for confounds suggests deficits may be smaller than previously reported but should be tracked longitudinally across illness progression and treatment.

Brain cortical thickness and surface area correlates of neurocognitive performance in patients with schizophrenia, bipolar disorder, and healthy adults.

Relationships between cortical brain structure and neurocognitive functioning have been reported in schizophrenia, but findings are inconclusive, and only a few studies in bipolar disorder have addressed this issue. This is the first study to directly compare relationships between cortical thickness and surface area with neurocognitive functioning in patients with schizophrenia (n = 117) and bipolar disorder (n = 121) and healthy controls (n = 192). MRI scans were obtained, and regional cortical thickness and surface area measurements were analyzed for relationships with test scores from 6 neurocognitive domains. In the combined sample, cortical thickness in the right rostral anterior cingulate was inversely related to working memory, and cortical surface area in four frontal and temporal regions were positively related to neurocognitive functioning. A positive relationship between left transverse temporal thickness and processing speed was specific to schizophrenia. A negative relationship between right temporal pole thickness and working memory was specific to bipolar disorder. In conclusion, significant cortical structure/function relationships were found in a large sample of healthy controls and patients with schizophrenia or bipolar disorder. The differences that were found between schizophrenia and bipolar may indicate differential relationship patterns in the two disorders, which may be of relevance for understanding the underlying pathophysiology.

Opposite relationships between cannabis use and neurocognitive functioning in bipolar disorder and schizophrenia.

BACKGROUND: Cannabis use is associated with altered neurocognitive functioning in severe mental disorders, but data are still inconclusive and there are no studies of bipolar disorder. The aim of this study was to investigate the association between cannabis use and neurocognition in bipolar disorder compared with schizophrenia in a naturalistic setting. METHOD: A total of 133 patients with bipolar disorder and 140 patients with schizophrenia underwent neuropsychological assessments and clinical characterization including measures of substance use. Relationships between cannabis users and neurocognitive function were explored in the two diagnostic groups. Possible interactions between diagnosis and cannabis use were investigated, and findings were controlled for possible confounders. RESULTS: In bipolar disorder subjects, cannabis use was associated with better neurocognitive function, but the opposite was the case for the schizophrenia subjects. There was a statistically significant interaction effect of diagnosis and cannabis use on focused attention (p=0.019), executive functioning (verbal fluency--set shifting) (p=0.009), logical memory-learning (p=0.007) and on logical memory-recall (p=0.004). These differences in neurocognitive function could not be explained by putative confounders. CONCLUSIONS: The findings suggest that cannabis use may be related to improved neurocognition in bipolar disorder and compromised neurocognition in schizophrenia. The results need to be replicated in independent samples, and may suggest different underlying disease mechanisms in the two disorders.

Illicit drug use in patients with psychotic disorders compared with that in the general population: a cross-sectional study.

OBJECTIVE: Prevalence estimates of illicit drug use in psychotic disorders vary between studies, and only a few studies compared prevalence estimates with those in the general population. METHOD: Cross-sectional study comparing 148 stable-phase patients with schizophrenia or bipolar disorder with 329 representative general citizens of Oslo. A total of 849 patients from the same hospital department in the same time period constituted a patient reference group. RESULTS: Lifetime illicit drug use was 44% higher (P < 0.001) in study patients than in the general population sample; while lifetime use of amphetamine/cocaine was 160% higher (P < 0.001). No differences were found between user groups for sociodemographic characteristics. CONCLUSION: Patients with psychotic disorders in stable phase had a markedly higher lifetime use of any illicit substance, especially amphetamine/cocaine, than the general population. They also seemed to use drugs more periodically. The same sociodemographic characteristics were associated with increased illicit drug use in both groups.

Backward-masking deficit in adolescents with schizophrenic disorders or attention deficit hyperactivity disorder.

OBJECTIVE: Backward masking is a cognitive task that involves the earliest phases of visual information processing. Disrupted task performance caused by a visual mask has been found repeatedly in schizophrenic patients; however, the specificity to schizophrenia of deficits in backward masking has received only limited study. METHOD: In this study 20 patients with early-onset schizophrenic disorders were compared to 20 adolescents with attention deficit hyperactivity disorder (ADHD) and 30 normal adolescents on a two-digit identification task in three backward-masking conditions: no mask, a short stimulus interval (33.0 msec), and a long stimulus interval (49.5 msec). RESULTS: The performance of the two groups of patients was similar, and both groups showed a statistically significant masking deficit after the long stimulus interval and a nearly significant deficit after the short stimulus interval in comparison with the normal subjects. CONCLUSIONS: Increased vulnerability to the masking stimulus was confirmed in schizophrenic subjects, but it is not specific to schizophrenia and is not accounted for by psychotic symptoms alone, since the subjects with ADHD performed similarly.

Covert visual attention in patients with early-onset schizophrenia.

The aim of the present study is to examine attentional costs (inhibition) in covert visual attention in a group of acutely ill adolescents with schizophrenia without long histories of neuroleptic treatment. Variations in reaction time were analyzed for possible age and sex differences. Adolescents with schizophrenia (n = 19) were compared to a group of ADHD subjects (n = 20) and a group of normally functioning adolescents (n = 30) on a measure of covert visual attention. The results support a hypothesis of abnormally rapid disengagement (reduced costs) in male adolescents with schizophrenia. Such an abnormality has also been found in adults with chronic schizophrenia. Whether this holds true for both sexes of adolescents with schizophrenia or is restricted to male subjects cannot be answered with certainty due to the small number of females with schizophrenia in our sample. Our findings indicate, however, that there are some general sex differences and some specific sex differences related to covert visual attention in adolescents with schizophrenia.

Honig's model of working memory and brain activation: an fMRI study.

The present study investigated changes in neuronal activation with fMRI related to Honig's model of working memory, which is much less studied compared with other working memory models. In contrast to other studies which have applied recognition procedures, the primary aim with the present study was to examine brain activation when subjects had to continuously recall and forget items held in working memory. The results showed that the mid-ventrolateral frontal cortex was particularly activated in the left hemisphere, whereas the mid-dorsolateral frontal cortex was particularly activated in the right hemisphere during execution of the working memory task. The findings are discussed in relation to process- and domain-specific accounts of working memory.

Auditory laterality and selective attention: normal performance in patients with early-onset schizophrenia.

In this study, auditory laterality and selective attention were examined in patients with early-onset schizophrenia using a dichotic listening (DL) test. Deficient performance on this test has repeatedly been found in adult patients with chronic schizophrenia, indicating abnormalities in left hemisphere function. The hypothesis in the present study was that subjects with early-onset schizophrenia manifest deficits in DL test performance similar to adult chronic patients. A group of 19 patients with early-onset schizophrenia were compared with a group of 20 adolescents with attention-deficit hyperactivity disorder and a group of 30 normal adolescents. Results indicated no significant differences between the three groups on any of the measures. Alternative hypotheses are put forth to explain the findings, among them that deficits in DL performance may be secondary to long-time illness and/or drug treatment, and that these deficits may become apparent only after interaction with maturational neurodevelopmental changes during adolescence.

Production and perception of word tones (pitch accents) in patients with left and right hemisphere damage.

The present paper addresses the question of the functional lateralization of tones in tone languages. Tonal perception and production of right-hemisphere-damaged (RHD) and left-hemisphere-damaged (LHD) speakers of East Norwegian were investigated. East Norwegian is a tone language with an opposition between two tones (pitch accents). The ability to distinguish auditorily between the two accents was normal in the RHD group but reduced in the LHD group. Tonal production was near normal in the RHD group, whereas the LHD group tended to have a production deficit.

Neurocognitive dimensions characterising patients with first-episode psychosis.

BACKGROUND: Assessment of neurocognitive dysfunction in schizophrenia is hampered by the multitude of tests used in the literature. AIMS: We aimed to identify the main dimensions of an assessment battery for patients with first-episode psychosis and to estimate the relationship between dimension scores and gender, age, education, diagnosis and symptoms. METHOD: Eight frequently used neuropsychological tests were used. We tested 219 patients 3 months after start of therapy or at remission, whichever occurred first. RESULTS: We identified five dimensions: working memory (WM); verbal learning (VL); executive function (EF); impulsivity (im); and motor speed (MS). Significant findings were that the MS score was higher for men, and the WM and VL scores were correlated with years of education. CONCLUSIONS: Neurocognitive function in first-episode psychosis is described by at least five independent dimensions.

TCF4 sequence variants and mRNA levels are associated with neurodevelopmental characteristics in psychotic disorders.

TCF4 is involved in neurodevelopment, and intergenic and intronic variants in or close to the TCF4 gene have been associated with susceptibility to schizophrenia. However, the functional role of TCF4 at the level of gene expression and relationship to severity of core psychotic phenotypes are not known. TCF4 mRNA expression level in peripheral blood was determined in a large sample of patients with psychosis spectrum disorders (n = 596) and healthy controls (n = 385). The previously identified TCF4 risk variants (rs12966547 (G), rs9960767 (C), rs4309482 (A), rs2958182 (T) and rs17512836 (C)) were tested for association with characteristic psychosis phenotypes, including neurocognitive traits, psychotic symptoms and structural magnetic resonance imaging brain morphometric measures, using a linear regression model. Further, we explored the association of additional 59 single nucleotide polymorphisms (SNPs) covering the TCF4 gene to these phenotypes. The rs12966547 and rs4309482 risk variants were associated with poorer verbal fluency in the total sample. There were significant associations of other TCF4 SNPs with negative symptoms, verbal learning, executive functioning and age at onset in psychotic patients and brain abnormalities in total sample. The TCF4 mRNA expression level was significantly increased in psychosis patients compared with controls and positively correlated with positive- and negative-symptom levels. The increase in TCF4 mRNA expression level in psychosis patients and the association of TCF4 SNPs with core psychotic phenotypes across clinical, cognitive and brain morphological domains support that common TCF4 variants are involved in psychosis pathology, probably related to abnormal neurodevelopment.