Astri J. Lundervold

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.

Differences between children and adolescents who commit suicide and their peers: A psychological autopsy of suicide victims compared to accident victims and a community sample

BackgroundThe purpose of this study was to gain knowledge about the circumstances related to suicide among children and adolescents 15 years and younger.MethodsWe conducted a psychological autopsy, collecting information from parents, hospital records and police reports on persons below the age of 16 who had committed suicide in Norway during a 12-year period (1993-2004) (n = 41). Those who committed suicide were compared with children and adolescents who were killed in accidents during the same time period (n = 43) and with a community sample. Results: Among the suicides 25% met the criteria for a psychiatric diagnosis and 30% had depressive symptoms at the time of death. Furthermore, 60% of the parents of the suicide victims reported the child experienced some kind of stressful conflict prior to death, whereas only 12% of the parents of the accident victims reported such conflicts.ConclusionOne in four suicide victims fulfilled the criteria for a psychiatric diagnosis. The level of sub-threshold depression and of stressful conflict experienced by youths who committed suicide did not appear to differ substantially from that of their peers, and therefore did not raise sufficient concern for referral to professional help.

A genome-wide association study of anorexia nervosa

Anorexia nervosa (AN) is a complex and heritable eating disorder characterized by dangerously low body weight. Neither candidate gene studies nor an initial genome-wide association study (GWAS) have yielded significant and replicated results. We performed a GWAS in 2907 cases with AN from 14 countries (15 sites) and 14 860 ancestrally matched controls as part of the Genetic Consortium for AN (GCAN) and the Wellcome Trust Case Control Consortium 3 (WTCCC3). Individual association analyses were conducted in each stratum and meta-analyzed across all 15 discovery data sets. Seventy-six (72 independent) single nucleotide polymorphisms were taken forward for in silico (two data sets) or de novo (13 data sets) replication genotyping in 2677 independent AN cases and 8629 European ancestry controls along with 458 AN cases and 421 controls from Japan. The final global meta-analysis across discovery and replication data sets comprised 5551 AN cases and 21 080 controls. AN subtype analyses (1606 AN restricting; 1445 AN binge–purge) were performed. No findings reached genome-wide significance. Two intronic variants were suggestively associated: rs9839776 (P=3.01 × 10−7) in SOX2OT and rs17030795 (P=5.84 × 10−6) in PPP3CA. Two additional signals were specific to Europeans: rs1523921 (P=5.76 × 10−6) between CUL3 and FAM124B and rs1886797 (P=8.05 × 10−6) near SPATA13. Comparing discovery with replication results, 76% of the effects were in the same direction, an observation highly unlikely to be due to chance (P=4 × 10−6), strongly suggesting that true findings exist but our sample, the largest yet reported, was underpowered for their detection. The accrual of large genotyped AN case-control samples should be an immediate priority for the field.

Impairment across executive functions in recurrent major depression.

Depression is associated with impairment of cognitive functions, and especially executive functions (EFs). Despite the fact that most depressed patients experience recurrence of episodes, the pattern and the severity of executive impairment have not been well characterized in this group of depressed patients. We asked if and to what extent these patients were impaired on a range of neuropsychological tests measuring EFs, and also when confounding factors were adjusted for. Forty-five patients (aged 19–51 years) with moderate to severe (Hamilton score >18) recurrent major depressive disorder (DSM-IV) were compared to 50 healthy controls matched on age, education, gender and intellectual abilities. The subjects were administered a set of neuropsychological tests that assesses sub-components of EFs. The depressed patients were impaired compared to the control group on all selected tests, with a severity of impairment within −1 standard deviation from the control group mean. The group difference was statistically significant for eight of the 10 EFs that were assessed. These were measures of verbal fluency, inhibition, working memory, set-maintenance and set-shifting. The group difference was still significant for all sub-components except for set-shifting (Wisconsin Card Sorting Test) and planning (Tower of London), when additional medication and retarded psychomotor speed was adjusted for. In conclusion, the depressed subjects were mildly impaired across a wide range of EFs. This may have a negative impact on everyday functioning for this group of patients.

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis

BACKGROUND Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156. FINDINGS Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohens d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohens d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5). INTERPRETATION With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING National Institutes of Health.

Increased Hippocampal Default Mode Synchronization during Rest in Middle-Aged and Elderly APOE ε4 Carriers: Relationships with Memory Performance

The apolipoprotein (APOE) ε4 allele is a strong genetic risk factor for Alzheimers disease (AD). Intrinsic fluctuations of brain activity measured by fMRI during rest may be sensitive to AD-related neuropathology. In particular, functional connectivity of the default-mode network (DMN) has gained recent attention as a possible biomarker of disease processes and associated memory decline in AD. Here, we tested the hypothesis of APOE-related alterations in DMN functional connectivity in 95 healthy individuals between 50 and 80 years of age, including 33 carriers of the ε4 allele. Based on previous studies, we hypothesized increased hippocampal DMN synchronization in APOE ε4 carriers. This was supported using independent component analysis in combination with a dual-regression approach for analysis of resting state data. Whole-brain analysis suggested effects also in other areas, including the posterior cingulate cortex, parietal cortex, and parahippocampal regions. DMN synchronization showed a negative correlation with performance on a test of memory functioning, suggesting a neurocognitive significance of the brain activity patterns during rest. Our findings indicate that increased genetic vulnerability for AD is reflected in increased hippocampal DMN synchronization during rest several years before clinical manifestation. We propose that the results reflect ε4-related failure in hippocampal decoupling, which might elevate the total hippocampal metabolic burden and increase the risk of cognitive decline and AD. The results provide an important confirmation of specific genotype effects on intrinsic fluctuations and support the use of functional connectivity indices as imaging-derived endophenotypes in the emerging field of imaging genetics.

Sleep and use of electronic devices in adolescence: results from a large population-based study

Objectives Adolescents spend increasingly more time on electronic devices, and sleep deficiency rising in adolescents constitutes a major public health concern. The aim of the present study was to investigate daytime screen use and use of electronic devices before bedtime in relation to sleep. Design A large cross-sectional population-based survey study from 2012, the youth@hordaland study, in Hordaland County in Norway. Setting Cross-sectional general community-based study. Participants 9846 adolescents from three age cohorts aged 16–19. The main independent variables were type and frequency of electronic devices at bedtime and hours of screen-time during leisure time. Outcomes Sleep variables calculated based on self-report including bedtime, rise time, time in bed, sleep duration, sleep onset latency and wake after sleep onset. Results Adolescents spent a large amount of time during the day and at bedtime using electronic devices. Daytime and bedtime use of electronic devices were both related to sleep measures, with an increased risk of short sleep duration, long sleep onset latency and increased sleep deficiency. A dose–response relationship emerged between sleep duration and use of electronic devices, exemplified by the association between PC use and risk of less than 5 h of sleep (OR=2.70, 95% CI 2.14 to 3.39), and comparable lower odds for 7–8 h of sleep (OR=1.64, 95% CI 1.38 to 1.96). Conclusions Use of electronic devices is frequent in adolescence, during the day as well as at bedtime. The results demonstrate a negative relation between use of technology and sleep, suggesting that recommendations on healthy media use could include restrictions on electronic devices.

Sleep patterns and insomnia among adolescents: a population-based study.

The aim of the current study was to examine sleep patterns and rates of insomnia in a population‐based study of adolescents aged 16–19 years. Gender differences in sleep patterns and insomnia, as well as a comparison of insomnia rates according to DSM‐IV, DSM‐V and quantitative criteria for insomnia (Behav. Res. Ther., 41, 2003, 427), were explored. We used a large population‐based study in Hordaland county in Norway, conducted in 2012. The sample included 10 220 adolescents aged 16–18 years (54% girls). Self‐reported sleep measurements included bedtime, rise time, time in bed, sleep duration, sleep efficiency, sleep onset latency, wake after sleep onset, rate and frequency and duration of difficulties initiating and maintaining sleep and rate and frequency of tiredness and sleepiness. The adolescents reported short sleep duration on weekdays (mean 6:25 hours), resulting in a sleep deficiency of about 2 h. A majority of the adolescents (65%) reported sleep onset latency exceeding 30 min. Girls reported longer sleep onset latency and a higher rate of insomnia than boys, while boys reported later bedtimes and a larger weekday–weekend discrepancy on several sleep parameters. Insomnia prevalence rates ranged from a total prevalence of 23.8 (DSM‐IV criteria), 18.5 (DSM‐V criteria) and 13.6% (quantitative criteria for insomnia). We conclude that short sleep duration, long sleep onset latency and insomnia were prevalent in adolescents. This warrants attention as a public health concern in this age group.

Executive function improvement upon remission of recurrent unipolar depression

AbstractThe aim of the study was to investigate the improvement of executive function measures upon recovery from unipolar depression. Thirty patients who suffered from recurrent major unipolar depression were retested with regard to their executive function approximately two years after an initial baseline examination. At baseline, patients were depressed (average 17–item HAM–D score 21.8), at retesting they were partially or totally recovered (average HAM–D score 8.2). There was a significant positive association between improvement on the HAM–D and improvement of executive function. In those with complete recovery, overall executive function and most examined executive function measures were no longer different from the baseline performance of healthy controls (with the possible exception of semantic fluency and Stroop Colour–word). In conclusion, recovery from major unipolar depression was accompanied by a recovery of many aspects of executive function to a normal level. Our findings support previous studies that have shown that neuropsychological impairment associated with long–standing depressive symptomatology is reversible (i. e. state–related) in recurrent unipolar depression.

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.