A. Payton

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.

A family-based and case-control association study of the dopamine D4 receptor gene and dopamine transporter gene in attention deficit hyperactivity disorder

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition of early childhood onset characterised by marked inattention, hyperactivity and impulsiveness. Molecular genetic investigations of ADHD have found positive associations with the 480-bp allele of a VNTR situated in the 3′ untranslated region of DAT1 and allele 7 of a VNTR in exon 3 of DRD4. A number of independent studies have attempted to replicate these findings but the results have been inconsistent. We used both family-based and case control approaches to examine these polymorphisms in a sample of 137 children diagnosed with ICD-10, DSM-IV or DSM-III-R ADHD. We found no evidence of association with the DAT1 polymorphism, despite a sample size that has up to 80% power to detect a previously reported effect size. We observed a significant increase in the DRD4 7 repeat allele amongst ADHD probands (21.7%) and their parents (18.9% in mothers, 22.3% in fathers), compared to ethnically matched controls (12.8%). However TDT analysis showed no preferential transmission of allele 7 to ADHD probands.

Brain-derived neurotrophic factor polymorphism Val66Met influences cognitive abilities in the elderly.

A functional brain‐derived neurotrophic factor (BDNF) gene polymorphism (Val66Met) that alters activity‐dependent secretion has previously been reported to influence cognitive functioning. A large proportion of these reports suggest that the Met allele, which results in reduced secretion of BDNF, impairs long‐term memory as a direct consequence of its influence on hippocampal function but has little influence on working memory. In contrast, other studies have found that the Met allele can also play a protective role in certain neurological conditions and is associated with improved non‐verbal reasoning skills in the elderly suggesting effects that appear disease, domain and age specific. We have investigated six haplotype‐tagging single nucleotide polymorphisms (SNPs) using a cohort of 722 elderly individuals who have completed cognitive tests that measured the domains of fluid intelligence, processing speed and memory. We found that the presence of the Met allele reduced cognitive performance on all cognitive tests. This reached nominal significance for tests of processing speed (P = 0.001), delayed recall (P = 0.037) and general intelligence (g) (P = 0.008). No association was observed between cognitive tests and any other SNPs once the Val66Met was adjusted for. Our results support initial findings that the Met allele is associated with reduced cognitive functioning. We found no evidence that the Met allele plays a protective role in older non‐demented individuals. Magnetic resonance imaging data collected from a subgroup of 61 volunteers showed that the left and right hippocampus were 5.0% and 3.9% smaller, respectively, in those possessing the Met allele, although only a non‐significant trend was observed.

Expression of hippocampal brain-derived neurotrophic factor and its receptors in Stanley consortium brains

Several lines of evidence implicate BDNF in the pathophysiology of psychiatric illness. BDNF polymorphisms have also been associated with the risk of schizophrenia and mood disorders. We therefore investigated whether levels of (pro)BDNF and receptor proteins, TrkB and p75, are altered in hippocampus in schizophrenia and mood disorder and whether polymorphisms in each gene influenced protein expression. Formalin-fixed paraffin-embedded hippocampal sections from subjects with schizophrenia, major depressive disorder (MDD), bipolar disorder (BPD) and non-psychiatric controls were obtained from the Stanley Foundation Neuropathology Consortium. (pro)BDNF, TrkB(T1) and p75 protein densities were quantified by immunoautoradiography and DNA extracted from each subject was used to determine the effect of genotype on protein expression. In MDD, reductions in (pro)BDNF were seen in all layers of the right but not the left hippocampus with no changes in the dentate gyrus. The pattern was similar but less marked for BPD. In addition, BPD but not MDD patients, had bilateral reductions in p75 in hippocampal layers but not in dentate gyrus. No changes in TrkB(T1) density were seen in any diagnosis. These findings suggest MDD and BPD may share impairment in (pro)BDNF expression. However, BPD may involve impairments of both (pro)BDNF and p75 receptor, whereas MDD may involve impaired (pro)BDNF alone. Moreover, the lateralisation of changes may indicate a role of asymmetry in vulnerability to MDD. Hippocampal (pro)BDNF and receptor levels were also affected by genotype, suggesting that allelic variations are important in the hippocampal abnormalities seen in these psychiatric disorders.

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.

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.

Absence of an association between HLA-DRB1*04 and rheumatoid arthritis in newly diagnosed cases from the community.

OBJECTIVES--To determine HLA-DR4 and DR1 allele frequencies in a series of patients with newly diagnosed early inflammatory arthritis. METHODS--HLA-DR1 and DR4 frequencies were determined by oligonucleotide typing of 208 patients classified as having either rheumatoid arthritis (RA) or undifferentiated inflammatory polyarthritis. RESULTS--The frequency of occurrence of DR4 in these patients with RA did not differ significantly from that in controls in the United Kingdom (42 v 37%). HLA-DR1 was increased in the group with inflammatory polyarthritis (25 v 18%). CONCLUSIONS--The frequency of DR4 is not increased in newly diagnosed community based patients with RA. This supports the hypothesis that DR4 is less important as a marker for susceptibility to RA than it is for disease persistence or severity.

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.

Cathepsin D exon 2 polymorphism associated with general intelligence in a healthy older population.

General intelligence is a heritable trait that is a risk factor for both the onset of dementia and the rate of cognitive decline in community-dwelling older persons. Previous studies screening for quantitative trait loci (QTLs) that influence general intelligence in healthy individuals have identified four loci, two of which are located within the genes insulin-like growth factor 2 receptor (IGF2R) and the Msx1 homeobox. Here, we report the finding of another QTL associated with general intelligence that is located within exon 2 of the cathepsin D (CTSD) gene. A group of 767 healthy adults with a follow-up period of over 15 years have been analyzed for cross-sectional and longitudinal trends in cognitive change using the Heim intelligence test score (AH4-1). We observed a significant association (P=0.01) between a functional C>T (Ala>Val) transition within exon 2 of the CTSD gene that increases the secretion of pro-CTSD from the cell, and the AH4-1 score at initial testing on entry to the longitudinal study. Interestingly, CTSD is transported by IGF2R from the trans Golgi network to the lysosome.

Variation in the dysbindin gene and normal cognitive function in three independent population samples

The association between DTNBP1 genotype and cognitive abilities was investigated in three population samples (1054 Scottish, 1806 Australian and 745 English) of varying age. There was evidence in each of the cohorts for association (P < 0.05) to single nucleotide polymorphisms (SNPs) and haplotypes previously shown to relate to cognition. By comparison with previous findings, these associations included measures of memory, and there was at best equivocal evidence of association with general cognitive ability. Of the SNPs typed in all three cohorts, rs2619528 and rs1011313 showed significant association with measures of executive function in two cohorts, rs1018381 showed significant association with verbal ability in one cohort and rs2619522 showed significance/marginal significance with tests of memory, speed and executive function in two cohorts. For all these SNPs, the direction and magnitude of the allelic effects were consistent between cohorts and with previous findings. In the English cohort, a previously untested SNP (rs742105) located in a distinct haplotype block upstream of the other SNPs showed the strongest significance (P < 0.01) for measures of memory but weaker significance for general cognitive ability. Our results therefore support involvement of the dysbindin gene in cognitive function, but further work is needed to clarify the specific functional variants involved and the cognitive abilities with which they are associated.