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.

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.

Prevalence and clinical correlates of insomnia in adults with attention-deficit hyperactivity disorder.

OBJECTIVE: To investigate the prevalence of insomnia in adults with Attention-deficit hyperactivity disorder (ADHD) and its association with clinical subtypes, current ADHD symptoms, and stimulant treatment. METHOD: We obtained diagnostic information, symptom rating scales and treatment history from clinically ascertained adult ADHD patients diagnosed according to DSM-IV criteria (n = 268, mean age 38.1 years) and randomly selected population controls (n = 202, mean age 36.5 years). The Bergen Insomnia Scale (BIS) was used to measure insomnia. ADHD symptom domains were self-rated using the Adult ADHD Self-Rating Scale. RESULTS: Insomnia was far more frequent among adults with ADHD (66.8%) than in the population controls (28.8%) (P < 0.001). Insomnia was more common in adults with the combined subtype than in those with the inattentive subtype (79.7% and 55.6%, respectively) (P = 0.003). For self-reported current ADHD symptoms, inattention was strongly correlated to insomnia. Patients currently using stimulant treatment for ADHD reported a lower total insomnia score compared to patients without medication (P < 0.05). CONCLUSION: Insomnia was highly prevalent among adults with ADHD. The lower insomnia score in patients on current stimulant treatment suggests that stimulant treatment is not associated with worsening of insomnia symptoms in adult ADHD 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.

Emotional development in children with tics: a longitudinal population-based study.

Children with tics often experience accompanying problems that may have more impact on their well being and quality of life than the tics themselves. The present study investigates characteristics and the course of associated problems. In a population-based follow-up study, we investigated the developmental trajectory of children with and without tics when they were 7-9 years old. Parents and teachers completed the strengths and difficulties questionnaire (SDQ) when the children were 7-9 years (wave 1) and 4 years later (wave 2). Using strict criteria, we identified 38 children with tics in the cohort of 4,025 children (0.94% of the total cohort) with a preponderance of boys (78.9%). 22 children (57.9%) in the group with tics had only motor tics, and 16 (42.1%) had both motor and vocal tics. Children with tics had significantly higher parent- and teacher-rated SDQ total difficulty scores and subscale scores in both waves. Children with tics experienced an increase in emotional problems and in peer problems between the first and the second wave. This study in a general population indicates that the presence of tics is associated with a range of internalizing and externalizing difficulties, as well as problems in peer relationships. Moreover, our study indicates that emotional and peer problems tend to increase over time in the group of children with tics.

Genome-wide association studies establish that human intelligence is highly heritable and polygenic.

General intelligence is an important human quantitative trait that accounts for much of the variation in diverse cognitive abilities. Individual differences in intelligence are strongly associated with many important life outcomes, including educational and occupational attainments, income, health and lifespan. Data from twin and family studies are consistent with a high heritability of intelligence, but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549,692 single nucleotide polymorphisms (SNPs) and detailed phenotypes on cognitive traits. We estimate that 40% of the variation in crystallized-type intelligence and 51% of the variation in fluid-type intelligence between individuals is accounted for by linkage disequilibrium between genotyped common SNP markers and unknown causal variants. These estimates provide lower bounds for the narrow-sense heritability of the traits. We partitioned genetic variation on individual chromosomes and found that, on average, longer chromosomes explain more variation. Finally, using just SNP data we predicted ∼1% of the variance of crystallized and fluid cognitive phenotypes in an independent sample (P=0.009 and 0.028, respectively). Our results unequivocally confirm that a substantial proportion of individual differences in human intelligence is due to genetic variation, and are consistent with many genes of small effects underlying the additive genetic influences on intelligence.

Emotional and behavioural problems in subgroups of children with chronic illness: results from a large-scale population study.

BACKGROUND: Children with chronic illness are known to have an increased risk of emotional and behavioural problems. In the present population-based study children with asthma, neurological disorders and other chronic illnesses were compared with children without chronic illnesses to assess differences in psychological presentation across illness groups. METHODS: A total of 537 children with parent-reported chronic illness in the Bergen Child Study were categorized into three groups: asthma, neurological disorders and other chronic illnesses. Emotional and behavioural problems were assessed by the Strengths and Difficulties Questionnaire. RESULTS: All three illness groups had an increased rate of emotional and behavioural problems, as well as increased probability of a psychiatric disorder compared with children without a chronic illness. Most children with asthma and other chronic illnesses did not have emotional and behavioural problems, and effect sizes were small in both groups. In children with neurological disorders the effect sizes ranged from moderate to large, with emotional problems, inattention hyperactivity and peer problems being the most frequent problems. CONCLUSIONS: The increased rate of emotional and behavioural problems in children with chronic illness, especially neurological disorders, emphasizes the importance of early detection of mental health problems in these children.

Association between catechol O-methyltransferase (COMT) haplotypes and severity of hyperactivity symptoms in adults.

It has been suggested that symptoms of attention-deficit/hyperactivity disorder (ADHD) is related to low dopamine levels in the prefrontal cortex. The enzyme catechol O-methyltransferase (COMT), which degrades dopamine and other catecholamines, is important for monoamine signaling in this brain-region, but genetic studies of the functional Val158Met (rs4680) polymorphism in ADHD have been inconsistent. However, recently it was shown that also common synonymous COMT variants modulate total COMT enzymatic activity by affecting the expression of the gene [Nackley et al. (2006); Science 314(5807):1930-1933]. We therefore hypothesized that analysis of haplotypes could reveal more about the association between COMT and ADHD symptoms than the Val158Met polymorphism alone. SNPs rs6269, rs4633, rs4818, and rs4680, tagging the common putative functional COMT haplotypes, were genotyped in 435 adult subjects with a clinical diagnosis of ADHD and 383 controls and analyzed for association with ADHD and the hyperactivity/impulsivity and inattention dimensions from the Adult ADHD Self-Report Scale (ASRS). All markers showed a trend for association with the hyperactivity/impulsivity scale, peaking at marker rs6269 (P = 0.007). Haplotype analysis revealed that the rs6269 risk allele tags the suggested high COMT-activity haplotype, which is associated with the highest hyperactivity/impulsivity score in our sample (P = 0.01). Our results also suggest that there is a stepwise decreased hyperactivity/impulsivity score associated with the proposed mid and low activity haplotypes described previously. In conclusion, we suggest that COMT haplotype variation is associated primarily with the hyperactivity/impulsivity dimension of ADHD and point to the importance of testing this hypothesis in future studies.

Behaviour-emotional characteristics of primary-school children rated as having language problems.

BACKGROUND: Primary-school teachers are expected to detect problems related to language function, but the teachers' evaluations may be heavily influenced by gender and classroom behaviour. AIM: To investigate the relationship between language problems (LPs) and behaviour-emotional problems as rated by primary-school teachers. METHODS: All participants participated in a population-based study, the Bergen Child Study (BCS). Teachers of 9,072 children and parents of 6,234 children completed forms containing questions pertaining to language function and the strengths and difficulties questionnaire (SDQ) to screen for behaviour-emotional problems. LP was defined as a score above the 95th percentile on the sum score of five language items. Children achieving a total SDQ score above the 90th percentile were defined as high scorers, indicating a high risk for behavioural-emotional problems. RESULTS: Based on teacher reports, 540 children were defined as having LP, more boys (N=366) than girls. Children defined as having LP were reported to have significantly higher scores on all SDQ subscales, and a higher total difficulty score than children without language problems (NLP). More LP boys than LP girls were defined as high scorers on the SDQ, with the highest effect size on the hyperactivity-inattention subscore. The agreement between teachers and parents was moderate to low, with the highest consensus of behaviour-emotional problems in children with LP. CONCLUSIONS: Primary-school children defined as having LP according to their teachers are frequently characterized by behavioural-emotional problems. Further assessment is warranted for primary-school children defined as having LP by their teachers.

Genetic analyses of dopamine related genes in adult ADHD patients suggest an association with the DRD5-microsatellite repeat, but not with DRD4 or SLC6A3 VNTRs.

Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable psychiatric disorder in children and adults. Recent meta-analyses have indicated an association between genes involved in dopaminergic signaling and childhood ADHD, but little is known about their possible role in adult ADHD. In this study of adults with ADHD, we evaluated the three most commonly studied ADHD candidate genetic polymorphisms; the dopamine receptor D4 (DRD4) exon 3 VNTR repeat, a microsatellite repeat 18.5 kb upstream of the DRD5 locus and the 3'UTR dopamine transporter SLC6A3 (DAT 1) VNTR. We examined 358 clinically diagnosed adult Norwegian ADHD patients (51% males) and 340 ethnically matched controls. We found a nominally significant overall association with adult ADHD for the DRD5 microsatellite marker (P = 0.04), and a trend toward increased risk associated with the 148-bp allele consistent with recent meta-analyses. The strongest overall association (P = 0.02) and increased risk for the 148-bp allele [odds ratio (OR) = 1.27 (95% CI: 1.00-1.61)] were seen in the inattentive and combined inattentive/hyperactive group as previously reported for childhood ADHD. No association was found for the DRD4 or SLC6A3 polymorphisms in this patient sample. In conclusion, our results among adults with a clinical diagnosis of ADHD support an association between ADHD and the DRD5 locus, but not the DRD4 or SLC6A3 loci. It is possible that the latter polymorphisms are associated with a transient form of ADHD with better long-term clinical outcome.

Autism traits: The importance of "co-morbid" problems for impairment and contact with services. Data from the Bergen Child Study.

BACKGROUND: Co-occurring problems are common in individuals with clinical autism spectrum disorder (ASD) but their relevance for impairment and contact with health services in ASD is largely unexplored. AIMS: We investigated the extent of co-occurring problems in children with high ASD traits from a total population sample. We explored the contribution of co-occurring problems to impairment and service contact, and whether there were children without co-occurring problems in this group; as proxy for "ASD only". METHODS AND PROCEDURES: Children screening positive on the Autism Spectrum Screening Questionnaire (ASSQ) were used as proxy for ASD. Attention Deficit/Hyperactivity Disorder (ADHD) and Oppositional Defiant Disorder (ODD) were operationalised using symptom counts. A parent or teacher report above the 95th percentile counted as "problem" present for other symptom domains. OUTCOMES AND RESULTS: 92% of ASSQ high-scorers had a minimum of two other problems. Emotional problems, ADHD symptoms and learning problems were the most commonly reported problems, also predicting impairment and contact with services. CONCLUSIONS AND IMPLICATIONS: Co-occurring problems were common in ASD screen positive children and contributed strongly to both impairment and to contact with services. Gender differences indicated that female symptoms were perceived as less impairing by parents and teachers.

Dichotic-listening performance and intracarotid injections of amobarbital in children and adolescents. Preoperative and postoperative comparisons.

BACKGROUND: Dichotic listening (DL) to consonant-vowel syllables is frequently used in clinical and experimental studies of brain laterality. However, the paradigm of consonant-vowel syllables has not been thoroughly validated through a comparison with injections of amobarbital sodium (Amytal). OBJECTIVE: To validate the DL test for hemisphere dominance preoperatively vs postoperatively with the results from intracarotid injections of amobarbital (i.e., the Wada test) in epileptic children and adolescents. DESIGN AND MAIN OUTCOME MEASURES: Patients were tested with DL preoperatively and at 6-month follow-up. Correct reports in the DL tests were entered in a stepwise discriminant analysis for calculation of correct classification of hemisphere dominance with the results from the injections of amobarbital as the grouping variable. Correct reports from the right and left ears on the consonant-vowel DL test were compared preoperatively and postoperatively, separated for the subjects with regard to language dominance in the left and right hemispheres. SETTING: The Department of Pediatrics, Ostra Hospital, University of Göteborg, Göteborg, Sweden. PATIENTS: Thirteen children and adolescents between the ages of 10 and 19 years, who were surgically treated for resistant epilepsy, were included in the study. The operated area corresponded with morphological changes and functional dysfunctions according to findings from computed tomography, magnetic resonance imaging, single photon emission computed tomography, and electroencephalography. RESULTS: The results of the Wada tests revealed that 10 subjects had left hemisphere language dominance, with 3 subjects having right hemisphere language dominance. All 3 subjects with right hemisphere language dominance showed a left ear advantage on the DL test preoperatively and postoperatively, with 8 and 7 of the 10 subjects with left hemisphere dominance showing a right ear advantage, preoperatively and postoperatively, respectively. However, according to discriminant analysis, knowledge of the DL performance led to a correct classification according to the Wada test results in 12 (92%) of the 13 subjects. CONCLUSIONS: A quantitative classification procedure like discriminant analysis may be more sensitive when predicting hemisphere speech dominance from DL data than a qualitative procedure based on the ear advantage dichotomy. The ear advantage dichotomy may actually introduce arbitrary left-right categories that do not correspond to the actual clustering of the data.

Planum temporale, planum parietale and dichotic listening in dyslexia.

A reduction or reversal of the normal leftward asymmetry of the planum temporale (PT) has been claimed to be typical of dyslexia, although some recent studies have challenged this view. In a population-based study of 20 right-handed dyslexic boys and 20 matched controls, we have measured the PT and the adjacent planum parietale (PP) region in sagittal magnetic resonance images. For the PT, mean left and right areas and asymmetry coefficients were compared. Since a PP area often could not be identified in one or both hemispheres, a qualitative comparison was used for this region. The total planar area (sum of PT and PP) was also compared between the two groups. A dichotic listening (DL) test with consonant-vowel syllables was administered to assess functional asymmetry of language. The results showed a mean leftward PT asymmetry in both the dyslexic and the control group, with no significant difference for the degree of PT asymmetry. Planned comparisons revealed however, a trend towards smaller left PT in the dyslexic group. In control children, but not in the dyslexic children, a significant correlation between PT asymmetry and reading was observed. A mean leftward asymmetry was also found for the total planar area, with no difference between the groups for the degree of asymmetry. Significantly fewer dyslexic children than control children showed a rightward asymmetry for the PP region. Both groups showed a normal right ear advantage on the DL task, with no significant difference for DL asymmetry. No significant correlation was observed between PT asymmetry and DL asymmetry. The present population-based study adds to recent reports of normal PT asymmetry in dyslexia, but indicates that subtle morphological abnormalities in the left planar area may be present in this condition.

Effects of electroconvulsive therapy (ECT) on thyroid function parameters.

Serum concentrations of thyroxine, triiodothyronine, TSH and prolactin were measured in 10 patients with affective disorders receiving ECT. Samples were drawn at -15 min, 0, +30 min, +60 min and +3 hr after ECT. A significant increase in both prolactin and TSH was observed 30 min after ECT. A small but significant decrease in triiodothyronine but no change in thyroxine was found in all post-ECT samples. The increase in TSH may be caused by an anti-dopaminergic effect of ECT at either the pituitary or the hypothalamic level.

Phantom limb imaginary fingertapping causes primary motor cortex activation: an fMRI study.

A conventional 1.0 T MR-scanner was used to detect signal intensity changes in blood oxygenation level dependent-sensitive acquisitions of motor cortex during real (left hand) and imaginary (right hand) fingertapping in a man who had his right arm amputated. The subject was instructed alternately to move the intact left hand fingers and to imagine tapping his 'fingers' on the amputated right hand. Activated areas were detected using a cross-correlation technique with superimposition of highly correlated voxels on to a corresponding high resolution, anatomical 3D image. Activation was observed in the right motor cortex during fingertapping with the intact left hand, and a corresponding activation in the left motor cortex for imaginary movements of the amputated right hand fingers.

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.

Temporal distribution of seizures in epilepsy.

A major problem in epileptology is why a seizure occurs at a particular moment in time. An initial step in solving this problem is a detailed analysis of the temporal distribution of seizures. Using methods and theories of stochastic processes, seizure patterns in a group of epileptic outpatients were examined for stationarity, randomness, dependency and periodicity in a prospective study. Sixteen of the 21 seizure diaries included in the study showed stationarity; 2 were non-stationary and 3 inconclusive. Eleven of the 16 stationary diaries were non-Poisson (P less than 0.005), indicating that in the majority of patients seizures did not occur randomly. The most frequently encountered phenomenon was seizure clustering. Clustering was considered when the diaries fulfilled all three criteria: (1) a positive R-test (P less than 0.001); (2) deviation from the fitted Poisson distribution towards clustering; and (3) the feature of an autoregressive process in the autocorrelogram plot. Dependency between seizure events was demonstrated in 8 of the 16 stationary diaries, computing first order transition probabilities. A detailed analysis of seizure occurrence is a major step towards a better understanding of the mechanisms underlying seizure precipitation. This is exemplified by our finding of a relation between seizure frequency and the menstrual cycle.

Multispectral analysis of the brain using magnetic resonance imaging.

The authors demonstrate an improved differentiation of the most common tissue types in the human brain and surrounding structures by quantitative validation using multispectral analysis of magnetic resonance images. This is made possible by a combination of a special training technique and an increase in the number of magnetic resonance channel images with different pulse acquisition parameters. The authors give a description of the tissue-specific multivariate statistical distributions of the pixel intensity values and discuss how their properties may be explored to improve the statistical modeling further. A statistical method to estimate the tissue-specific longitudinal and transverse relaxation times is also given. It is concluded that multispectral analysis of magnetic resonance images is a valuable tool to recognize the most common normal tissue types in the brain and surrounding structures.