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.

GWAS-based pathway analysis differentiates between fluid and crystallized intelligence.

Cognitive abilities vary among people. About 40-50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) - the ability to reason in novel situations - and general crystallized intelligence (gC) - the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene- and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long-term depression (LTD) seemed to underlie gC. Thus, this study supports the gF-gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.

Human cognitive ability is influenced by genetic variation in components of postsynaptic signalling complexes assembled by NMDA receptors and MAGUK proteins.

Differences in general cognitive ability (intelligence) account for approximately half of the variation in any large battery of cognitive tests and are predictive of important life events including health. Genome-wide analyses of common single-nucleotide polymorphisms indicate that they jointly tag between a quarter and a half of the variance in intelligence. However, no single polymorphism has been reliably associated with variation in intelligence. It remains possible that these many small effects might be aggregated in networks of functionally linked genes. Here, we tested a network of 1461 genes in the postsynaptic density and associated complexes for an enriched association with intelligence. These were ascertained in 3511 individuals (the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium) phenotyped for general cognitive ability, fluid cognitive ability, crystallised cognitive ability, memory and speed of processing. By analysing the results of a genome wide association study (GWAS) using Gene Set Enrichment Analysis, a significant enrichment was found for fluid cognitive ability for the proteins found in the complexes of N-methyl-D-aspartate receptor complex; P=0.002. Replication was sought in two additional cohorts (N=670 and 2062). A meta-analytic P-value of 0.003 was found when these were combined with the CAGES consortium. The results suggest that genetic variation in the macromolecular machines formed by membrane-associated guanylate kinase (MAGUK) scaffold proteins and their interaction partners contributes to variation in intelligence.

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.

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.

Multimodal imaging in mild cognitive impairment: Metabolism, morphometry and diffusion of the temporal-parietal memory network.

This study compared sensitivity of FDG-PET, MR morphometry, and diffusion tensor imaging (DTI) derived fractional anisotropy (FA) measures to diagnosis and memory function in mild cognitive impairment (MCI). Patients (n=44) and normal controls (NC, n=22) underwent FDG-PET and MRI scanning yielding measures of metabolism, morphometry and FA in nine temporal and parietal areas affected by Alzheimer's disease and involved in the episodic memory network. Patients also underwent memory testing (RAVLT). Logistic regression analysis yielded 100% diagnostic accuracy when all methods and ROIs were combined, but none of the variables then served as unique predictors. Within separate ROIs, diagnostic accuracy for the methods combined ranged from 65.6% (parahippocampal gyrus) to 73.4 (inferior parietal cortex). Morphometry predicted diagnostic group for most ROIs. PET and FA did not uniquely predict group, but a trend was seen for the precuneus metabolism. For the MCI group, stepwise regression analyses predicting memory scores were performed with the same methods and ROIs. Hippocampal volume and FA of the retrosplenial WM predicted learning, and hippocampal metabolism and parahippocampal cortical thickness predicted 5 minute recall. No variable predicted 30 minute recall independently of learning. In conclusion, higher diagnostic accuracy was achieved when multiple methods and ROIs were combined, but morphometry showed superior diagnostic sensitivity. Metabolism, morphometry and FA all uniquely explained memory performance, making a multi-modal approach superior. Memory variation in MCI is likely related to conversion risk, and the results indicate potential for improved predictive power by the use of multimodal imaging.

Morphometric changes in the episodic memory network and tau pathologic features correlate with memory performance in patients with mild cognitive impairment.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) may affect several cognitive domains, including attention and reasoning, but is often first characterized by memory deficits. The purpose of this study was to ask these 2 questions: 1) Can levels of CSF tau proteins and amyloid beta 42 peptide explain thinning of the cerebral cortex in patients with MCI? 2) How are brain morphometry, CSF biomarkers, and apolipoprotein E (APOE) allelic variation related to episodic memory function in MCI? MATERIALS AND METHODS: Hippocampal volume and cortical thickness were estimated by MR imaging and compared for patients with MCI (n = 18) and healthy controls (n = 18). In addition, regions of interest (ROIs) were selected in areas where the MCI group had atrophy and which overlapped with the episodic memory network (temporal, entorhinal, inferior parietal, precuneus/posterior cingulate, and frontal). Relationships among morphometry, CSF biomarkers, APOE, and memory were tested. The analyses were repeated with an independent sample of patients with MCI (n = 19). RESULTS: Patients with MCI and pathologic CSF values had hippocampal atrophy. However, both patients with pathologic and patients with nonpathologic CSF had a thinner cortex outside the hippocampal area. CSF pathology was related to hippocampal volume, whereas relationships with cortical thickness were found mainly in one of the samples. Morphometry correlated robustly with memory performance across MCI samples, whereas less stable results were found for tau protein. CONCLUSION: The differences in hippocampal volume between the MCI and the healthy control groups were only found in patients with pathologic CSF biomarkers, whereas differences in cortical thickness were also found for patients without such pathologic features. Morphometry in areas in the episodic memory network was robustly correlated with memory performance. It is speculated that atrophy in these areas may be associated with the memory problems seen in MCI.

White matter lesion severity is associated with reduced cognitive performances in patients with normal CSF Abeta42 levels.

OBJECTIVE: To identify possible associations between white matter lesions (WML) and cognition in patients with memory complaints, stratified in groups with normal and low cerebrospinal fluid (CSF) Abeta42 values. MATERIAL AND METHODS: 215 consecutive patients with subjective memory complaints were retrospectively included. Patients were stratified into two groups with normal (n = 127) or low (n = 88) CSF Abeta42 levels (cut-off is 450 ng/l). Cognitive scores from the Mini-Mental State Examination (MMSE) and the Neurobehavioral Cognitive Status Examination (Cognistat) were used as continuous dependent variables in linear regression. WML load was used as a continuous independent variable and was scored with a visual rating scale. The regression model was corrected for possible confounding factors. RESULTS: WML were significantly associated with MMSE and all Cognistat subscores except language (repetition and naming) and attention in patients with normal CSF Abeta42 levels. No significant associations were observed in patients with low CSF Abeta42. CONCLUSIONS: WML were associated with affection of multiple cognitive domains, including delayed recall and executive functions, in patients with normal CSF Abeta42 levels. The lack of such associations for patients with low CSF Abeta42 (i.e. with evidence for amyloid deposition), suggests that amyloid pathology may obscure cognitive effects of WML.

Nicotine receptor gene CHRNA4 modulates early event-related potentials in auditory and visual oddball target detection tasks.

The present study seeks to identify effects of a common genetic polymorphism in the human nicotinic alpha4beta2 receptor on components of the cognitive event-related potentials in auditory and visual modalities. The same sense thymine-to-cytosine polymorphism (c.1629T-C; Ser543Ser) was shown to preferentially modulate early components in both modalities. Specifically, the auditory N1 component amplitude was higher for T allele homozygotes than for C allele carriers. The visual P1 component revealed the same pattern of significant polymorphic modulation, but the later N1 amplitude differences were only marginally significant. There was no reliable indication of interactions between genotype and task factors. Parallel modulation of early latency modality-specific event-related potential (ERP) components in vision and audition may indicate that the CHRNA4 polymorphism affects factors that are common to top-down modulation of sensory processing across modalities.

Diaschisis after thalamic stroke: a comparison of metabolic and structural changes in a patient with amnesic syndrome.

INTRODUCTION: We present a patient with a left anteromedial thalamic lesion with an amnesic syndrome. The patient underwent neuropsychological testing, cerebrospinal fluid (CSF) analyses, magnetic resonance imaging (MRI) [T2, flair, and diffusion tensor imaging (DTI)] and [18F]-2-fluoro-deoxy-d-glucose positron emission tomography (FDG-PET) to assess indirect effects of thalamic lesions on cortical function. CASE REPORT: A 67-year-old right-handed woman was admitted to a university-based memory unit because of memory and concentration problems. Neuropsychological testing revealed dysfunction of episodic memory, semantic memory and working memory. General intellectual function and attention capacity were preserved. MRI revealed an anteromedial thalamic lesion in the left hemisphere. FDG-PET showed decreased uptake in the frontal, parietal and temporal lobes of the left hemisphere. Regions of interest (ROI) in white matter were selected and left and right hemispheres were compared. Fractional anisotropy (FA) in ROI representing thalamo-cortical connections were decreased in the left hemisphere when compared with the right. CONCLUSION: The results show the importance of a network that include the anterior and dorsomedian nuclei, which influence the activity in areas of the cortex responsible for memory processes. The imaging findings suggest that areas of cortical diaschisis after thalamic infarction correspond to areas affected by thalamo-cortical fibre loss as measured with FA.

Size does matter in the long run: hippocampal and cortical volume predict recall across weeks.

OBJECTIVE: To study the morphometric determinants of recall of verbal material for an extended period in an adult lifespan sample. METHODS: Healthy adults of varying ages were studied using automated segmentation of MRI scans with volumes of hippocampus, cortex, and white matter, and verbal memory tests assessing recall after 5 minutes, 30 minutes, and a mean period of 11 weeks. Stepwise regression analyses were performed with 5 minutes, 30 minutes, and 11-week recall as the dependent variables. Hippocampal, cortical, and white matter volumes were included in the initial set of predictor variables in each case, and the analyses were repeated with age as an additional predictor variable. RESULTS: When age was not included, cortical volume was the only variable predicting recall after 5 and 30 minutes, whereas hippocampal and cortical volumes predicted recall after 11 weeks. When age was included in the model, this was the only variable predicting recall after 5 and 30 minutes, whereas age and hippocampus gave contributions in prediction of recall after several weeks. CONCLUSION: This study supports a critical role of cortical and hippocampal size in recall. Hippocampal size seems more important in recall after 11 weeks than after a shorter time interval.

Failure to confirm neurotoxic impairment using cerebral magnetic resonance imaging on solvent-exposed workers.

OBJECTIVES: The study aimed at assessing signs of nervous system impairment by cerebral magnetic resonance imaging (MRI) among workers with a history of long-term exposure to mixtures of organic solvents. METHODS: Thirty-six workers (mean age 44.1 years) with at least 10 (mean 23.9) years of occupational exposure to solvents and pair-matched referents with no former solvent exposure went through a blind, random-order investigation of cerebral MRI, performed with a 1.5-tesla scanner. RESULTS: Linear measurements of the MRI tomograms showed a slight tendency toward wider ventricles and broader cortical sulci in the reference group. Visual evaluation of the MRI by 2 experienced neuroradiologists showed no significant difference between the groups; however, there was substantial interobserver variability. CONCLUSIONS: The MRI findings of this study do not support the hypothesis that long-term low-level occupational exposure to organic solvents results in the development of brain atrophy, or specific MRI signal changes in the region of the basal ganglia and thalami.

Brain regions involved in spatial frequency discrimination: evidence from fMRI.

The cortical areas underlying successive spatial-frequency discrimination were explored using functional magnetic resonance imaging (fMRI). In a steady-state, block-design paradigm, 12 subjects viewed a single fixation cross during a rest period, followed by an activation period consisting of the presentation of horizontal (distractors) and vertical (targets) sinewave gratings. Two tasks were performed: in the control task, subjects pressed a button after the second vertical grating was presented within each trial; in the discrimination task, subjects decided which target grating had the higher spatial frequency. Post-processing consisted of off-line image registration to correct for head motion, spatial and temporal smoothing, and cross-correlation between each voxel time course and a phase-shifted stimulus time profile. The results indicate that striate, extrastriate, parietal, and prefrontal areas show significant BOLD (blood oxygen level dependent) effects during both discrimination and control tasks, with consistently higher activity levels in the discrimination task.

Information processing deficits in head injury assessed with ERPs reflecting early and late processing stages.

ERPs provide informative measures of slowed information processing in head injury. While several studies have reported changes in long latency ERPs (N2, P3) in head injury, the data on early ERP components related to attention selection are inconclusive. The problem may be partly methodological because the standard oddball paradigm does not give an adequate basis for discriminating components contributing to the N1 and P2 waveforms. Following a suggestion by Garcia-Larrea et al. [10: Garcia-Larrea L, Lukasziewicz A-C, Maugière F. Revisiting the oddball paradigm. Non-target vs neutral stimuli and the evaluation of ERP attention effects. Neuropsychologia 1992;30:723-741] we used an extended oddball paradigm to study measures of early processing (N1-average, P250) as well as conventional cognitive ERPs (N1, P2, N2, P3) in a group of head injured patients and controls. We found evidence of deficits in early processing of neutral and non-target stimuli in the patient group, and interpret the findings as an indication that the patients are less efficient in terminating processing of irrelevant stimuli. The results further indicate that processing deviations affect both target and non-target stimuli in the oddball paradigm and thus the allocation of attention in the task as a whole.

ERP indices of resource allocation difficulties in mild head injury.

This study examined the hypothesis that distractibility is a characteristic sequela of mild closed head injury (MHI). The Minnesota Multiphasic Personality Inventory (MMPI-2) was used to study whether comorbid stress-related symptoms are associated with behavioral and electrophysiological indexes of attention. Event-related potentials (ERPs) and performance (reaction time, accuracy) were studied in patients with MHI (n = 20), patients with frontal lesions (n = 14), and healthy controls (n = 20) during a three-tone oddball task. Participants were instructed to detect rare target (2000 Hz) tones, and to withhold responding to equally rare distractor (500 Hz) tones and frequently occurring standard (1000 Hz) tones. All groups distinguished the two classes of deviants as indicated by the larger P3 amplitude to target relative to distractor tones. This indicates that the group with MHI was capable of differential allocation of attentional resources to target and non-target events. However, impaired performance and attenuated ERP amplitudes to both classes of deviants relative to patients with frontal lesions and controls, suggest limited availability, or expenditure of the resources needed for adequate task performance. In the group with MHI, both P3 amplitude and reaction time (RT) were significantly related to subjectively reported distress. The difference in RT disappeared, whereas the P3 amplitude differences between the patient groups remained when adjusting for level of distress.

ERP indicators of disturbed attention in mild closed head injury: a frontal lobe syndrome?

The purpose of the study was to examine the hypothesis that distractibility is a fundamental characteristic of mild closed head injury (MHI). The claim that cognitive symptoms in MHI are due to a mild type of frontotemporal injury was also investigated. Cognitive event-related potentials (ERPs), accuracy and reaction time to target stimuli in a dichotic listening paradigm, and neuropsychological test results were studied in patients with MHI (N = 15), patients with verified frontal lobe damage (N = 10), and healthy controls (N = 13). Information processing reflecting target detection (N2, P3b) and sustained selective attention (processing negativity) was studied. The MHI and frontal patients did not differ on behavioral measures, except that the MHI group had significantly longer reaction times to target stimuli in the ERP task. Both patient groups had deviant ERPs compared with controls, but their ERP patterns differed in important respects. Contrary to expectations, the MHI patients had the most abnormal ERPs. They showed significantly smaller N2 and Nd amplitudes than frontal patients and controls, indicating that the mediating cognitive mechanisms were not equivalent in MHI and frontal injury. The data suggest that MHI patients allocated less processing resources to the task than either the control subjects or the patients with frontal lobe damage.

Cognitive event-related potentials in neuropsychological assessment.

Neuropsychology is a behavioral approach to studying the brain, and an integration of neuropsychology with on-line processing measures of brain function is important for advancing the understanding of brain-behavior relationships. Cognitive event-related potentials (ERPs) are on-line processing measures that are of interest to neuropsychologists because they are linked to familiar neuropsychological test paradigms and because they have reached a degree of standardization sufficient to make them applicable in individual assessment. A selective review of cognitive ERPs is given, focusing on studies of attention in the oddball paradigm and arguing that an adequate assessment of attention is basic in understanding higher order cognitive functions. General principles for using ERP data to supplement and clarify neuropsychological analysis are discussed, and available evidence on dementia and traumatic head injury is reviewed. It is concluded that ERPs are a useful supplement to neuropsychological assessment. Although diagnostic use of ERPs must be guarded because of limited standardization and validation, information-processing analysis with ERPs may aid significantly in interpretation of behavioral data.

Electrophysiological localization of brain regions involved in perceptual memory.

Event-related potentials (ERP) were recorded during perceptual discrimination and short-term memory, varying the interstimulus interval (1-10 s) in delayed spatial frequency discrimination. Accuracy of discrimination remained unimpaired across this time interval, but choice reaction times increased. A brain source localization (BESA) model showed that the activity of the parietal and right temporal sources increased with long retention intervals in a sequential activation pattern where a long-latency component of the parietal source specific to the memory condition was observed, the latency of which matched a memory-related increase in choice reaction times in the cognitive task. It is suggested that the temporal sources are involved in encoding and storage of visual information, and the parietal source is involved in memory retrieval.