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.

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.

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.

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.

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.

Event-related potentials to stimuli with emotional impact in posttraumatic stress patients.

BACKGROUND: Psychophysiological research has given conflicting results with respect to whether the abnormal physiologic responses observed in posttraumatic stress disorder (PTSD) reflect a general abnormality or are linked to trauma-related stimuli. We studied differences in the central nervous processing of words with emotional impact in survivors after a ship fire disaster. METHODS: Event-related potentials were studied in 11 survivors with posttraumatic stress pathology, and compared with 9 survivors without such pathology. Nonwords and words with negative or positive emotional valence were used as distractors in a P3 oddball paradigm. RESULTS: PTSD subjects had increased N1 latency to standard tones and increased positive amplitude to both words and nonwords compared with controls, occurring between 200 and 350 msec after stimulus onset. The amplitudes to emotionally meaningful words were significantly related to Clinician-Administered PTSD Scale-assessed PTSD dimensions, in particular avoidance and arousal. CONCLUSIONS: The abnormality in information processing observed in PTSD patients seems in part to be linked with increased attention, in part with emotional responses to the trauma. Intrusion was mainly related to the processing of nonwords, while arousal and avoidance were related to event-related potential amplitudes to emotionally meaningful words, suggesting that intrusion has a different neurobiological basis than arousal and avoidance.

Focal retrograde amnesia associated with vascular headache.

We report the case of a 42-year-old man with repeated attacks of headache associated with retrograde amnesia. Neuropsychological tests before and after the major episode of amnesia showed mild neuropsychological deficits but with spared anterograde memory and learning functions. The amnesia was dense for a period of 15-20 years and included people and events (public and private). There was also a suggestion of amnesia for learned skills. Neurologically he had mild clinical signs and focal EEG-abnormalities in the left fronto-temporal region, but CT, MRI, and SPECT showed no abnormality. Five years after the onset of amnesia there was no recovery of the retrograde memory deficit, but a PET (glucose) scan was normal and neuropsychological testing showed no deficits. An association with migraine has been reported for some non-classical amnesias, but this is the first case of selective retrograde amnesia in a patient with headache as a primary neurological diagnosis.

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.

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.

Event related potentials and serial list picture memory in Parkinson's patients.

Two experiments examined short-term memory for order information in six patients diagnosed with Parkinson's disease (PD) and six control subjects while event related potentials (ERPs) were recorded. The subjects were tested for recognition of abstract spatial designs and words after a 5 s retention interval. The PD patients failed to respond in 29% of all trials, but the overall accuracy was similar to that in the control group when these trials were excluded. The corresponding ERP results show serial position variations both after presentation of the probe items, and after presentation of the memory set items. The amplitudes were generally lower at all positions for the PD patients at the parietal midline electrode, and the amplitudes were similar for both groups at the frontal electrode. Also, the ERP latencies were significantly slower for the PD patients than for the control group at all conditions. Indirectly the data are consistent with an interpretation of cognitive deficit in PD stressing attention resources.

The relation between integration, sequence of information, short-term memory, and Token Test performance of aphasic subjects.

Fifty-two aphasic patients were tested with a modification of part II of the Token Test. Three experimental variables were investigated: (a) the temporal sequence of information in the instructions, comparing instructions with preposition versus the ordinary postoposition of noun; (b) the spatial organization of the target objects, comparing an organization with color as the primary organizational factor to the ordinary organization primarily based on form; and (c) the specific timing of the presentation of instructions and tokens, comparing a successive presentation of instructions and tokens to the ordinary simultaneous presentation. Neither token organization nor instruction timing affected test performance. Sequence of information was important, however, and it is suggested that the effect can be explained by better opportunities for integration for preposition versus postposition instructions. The patients were also tested with several memory-span tests, and these results are related to those from the modified Token Test.

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.