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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

The effect of gender on emotion perception in schizophrenia and bipolar disorder.

OBJECTIVE: Impaired emotion perception is documented for schizophrenia, but findings have been mixed for bipolar disorder. In healthy samples females perform better than males. This study compared emotion perception in schizophrenia and bipolar disorder and investigated the effects of gender. METHOD: Visual (facial pictures) and auditory (sentences) emotional stimuli were presented for identification and discrimination in groups of participants with schizophrenia, bipolar disorder and healthy controls. RESULTS: Visual emotion perception was unimpaired in both clinical groups, but the schizophrenia sample showed reduced auditory emotion perception. Healthy males and male schizophrenia subjects performed worse than their female counterparts, whereas there were no gender differences within the bipolar group. CONCLUSION: A disease-specific auditory emotion processing deficit was confirmed in schizophrenia, especially for males. Participants with bipolar disorder performed unimpaired.

Neuropsychological test profiles in schizophrenia and non-psychotic depression.

OBJECTIVE: The study examined to what degree schizophrenia is characterized by a neuropsychological (NP) test profile specific in shape and level compared with depression and normal functioning. METHOD: Fifty-three patients with schizophrenia, 45 with non-psychotic depression, and 50 normals were assessed with a comprehensive NP test battery and clinical instruments. NP test scores were factor analyzed into seven composite scores. RESULTS: Schizophrenia patients performed significantly below normals across all seven composite scores, whereas depression patients were impaired in two. Verbal memory was most impaired. Sixty-two percent of schizophrenia patients were moderately or severely impaired, the corresponding figure for depression was 28%. Impairment was moderately associated with IQ level and clinical symptom load in schizophrenia, but not in depression. CONCLUSION: Schizophrenia is characterized by deficits across a wide range of NP functions. Thirty-eight percent of the patients are within normal limits. A mild and limited NP disturbance is apparent in depression.

Cortisol level predicts executive and memory function in depression, symptom level predicts psychomotor speed.

OBJECTIVE: On a group level depression is related to hypercortisolism and to psychomotor retardation, executive dysfunction and memory impairment. However, intra-group heterogeneity is substantial. Why some are impaired while others remain in the normal range, is not clear. The present study aims at discerning the relative contribution of present symptom severity and hypercortisolism to impairment in the three domains of cognition. METHOD: Morning saliva cortisol was measured in 26 subjects with recurrent major depression prior to a neuropsychological examination with tests known to be sensitive to cognitive impairment in depression. RESULTS: Cortisol level correlated with executive dysfunction and post-encoding memory deficits, but not with processing speed. Depression level correlated with processing speed. These patterns remained significant after controlling for confounders through partial correlations. CONCLUSION: The association between cortisol and cognition is not an artifact of psychiatric symptom load. High level of saliva cortisol is associated with aspects of cognition that can be dissociated from psychomotor retardation, which is dependent on symptom load.

Congenital hypothyroidism: no adverse effects of high dose thyroxine treatment on adult memory, attention, and behaviour.

BACKGROUND: In congenital hypothyroidism (CH) it has been questioned whether high dose thyroxine replacement therapy has detrimental effects on memory, attention, and behaviour. AIMS: To describe memory, attention, and behaviour problems in young adults with CH, and to study possible negative effects of high dose thyroxine replacement therapy. METHODS: A cohort based follow up study of 49 young adults (mean age 20 years) with early treated CH, and sibling controls (n = 41). RESULTS: Controlled for age and sex, the CH group attained significantly lower scores than sibling controls on some tests of memory (Wechsler Logical Memory part II: 12.9 versus 17.8; difference 5.2, 95% CI 3.6 to 6.8) and attention (Wechsler Freedom From Distractibility factor: 95.6 versus 104.8; difference 9.9, 95% CI 6.4 to 13.4). They rated themselves with more behaviour problems than did sibling controls (52.7 versus 44.7; difference -7.6, 95% CI -11.2 to -4.0) on the Achenbach Self Report. A high thyroxine starting dose, high serum thyroxine treatment levels during the first six childhood years, and high levels at assessment had no adverse effects on outcome measures at age 20. On the contrary, the results suggest better outcome with higher childhood treatment levels. CONCLUSIONS: Long term outcome revealed deficits in some aspects of memory, attention, and behaviour in young adults with CH relative to sibling controls. No adverse effects of high dose thyroxine therapy were found on measures of memory, attention, and behaviour problems.

General psychopathology is more important for executive functioning than diagnosis.

OBJECTIVE: Impaired executive functioning (EF) has often been reported in patients with major depression or schizophrenia. We hypothesize that the variance in EF is more affected by level of general psychopathology than by diagnosis. METHOD: Forty-three patients with major depression and 47 with schizophrenia were included. EF was measured with Wisconsin Card Sorting Test, Stroop Colour Word Test, Paced Auditory Serial Addition Test, Digits Backwards and Controlled Oral Word Association Test. The level of general psychopathology was measured with Brief Psychiatric Rating Scale - Expanded and Positive and Negative Syndrome Scale, the General psychopathology subscale. RESULTS: The level of general psychopathology predicted more of the variance in EF than diagnosis. In multivariate analyses, the effect of general psychopathology on EF was more robust for adjustment for diagnosis than vice versa. CONCLUSION: Future research on cognitive functioning in psychiatric patients should include level of general psychopathology to avoid overemphasising effects of diagnoses.

Attention profile in schizophrenia compared with depression: differential effects of processing speed, selective attention and vigilance.

OBJECTIVE: The aim of the study is to investigate whether subjects with schizophrenia and major depression display attention deficits for different reasons. METHOD: Subjects with schizophrenia (n = 53), recurrent major depression (n = 50) and normal controls (n = 50) were administered with 11 measures of processing speed, selective attention and vigilance. Indices of basal speed, speeded attention, non-speeded attention and vigilance were computed. RESULTS: Both clinical groups were impaired on all chronometric tests. The schizophrenic subjects were also more impaired on speeded attention compared with basal processing speed. Only the schizophrenics were impaired on the non-speeded measures of selective attention. Compared with the schizophrenics, the depressives showed a decrement in vigilance. CONCLUSION: Reduced performance on attention tests in major depression is because of a non-specific speed reduction and loss of vigilance consistent with lack of effort. In addition to generally impaired processing speed, the schizophrenic subjects exposed a deficit in selective attention, indicating executive dysfunction.

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.