Perceptual speed does not cause intelligence, and intelligence does not cause perceptual speed

There is ongoing debate whether the efficiency of local cognitive processes leads to global cognitive ability or whether global ability feeds the efficiency of basic processes. A prominent example is the well-replicated association between inspection time (IT), a measure of perceptual discrimination speed, and intelligence (IQ), where it is not known whether increased speed is a cause or consequence of high IQ. We investigated the direction of causation between IT and IQ in 2012 genetically related subjects from Australia and The Netherlands. Models in which the reliable variance of each observed variable was specified as a latent trait showed IT correlations of -0.44 and -0.33 with respective Performance and Verbal IQ; heritabilities were 57% (IT), 83% (PIQ) and 77% (VIQ). Directional causation models provided poor fits to the data, with covariation best explained by pleiotropic genes (influencing variation in both IT and IQ). This finding of a common genetic factor provides a better target for identifying genes involved in cognition than genes which are unique to specific traits.     

Genetic sources of covariation among P3(00) and online performance variables in a delayed-response working memory task

Genetic and environmental sources of covariation among the P3(00) and online performance elicited in a delayed-response working memory task, and psychometric IQ assessed by the multidimensional aptitude battery, were examined in an adolescent twin sample. An association between frontal P3 latency and task performance (phenotypic r=-0.33; genotypic r=-0.49) was indicated, with genes (i.e. twin status) accounting for a large part of the covariation (>70%). In contrast, genes influencing P3 amplitude mediated only a small part (2%) of the total genetic variation in task performance. While task performance mediated 15% of the total genetic variation in IQ (phenotypic r=0.22; genotypic r=0.39) there was no association between P3 latency and IQ or P3 amplitude with IQ. The findings provide some insight into the inter-relationships among psychophysiological, performance and psychometric measures of cognitive ability, and provide support for a levels-of-processing genetic model of cognition where genes act on specific sub-components of cognitive processes.     

Genetic correlates of brain aging on MRI and cognitive test measures: a genome-wide association and linkage analysis in the Framingham study

Background

Brain magnetic resonance imaging (MRI) and cognitive tests can identify heritable endophenotypes associated with an increased risk of developing stroke, dementia and Alzheimer's disease (AD). We conducted a genome-wide association (GWA) and linkage analysis exploring the genetic basis of these endophenotypes in a community-based sample.

Methods

A total of 705 stroke- and dementia-free Framingham participants (age 62 +9 yrs, 50% male) who underwent volumetric brain MRI and cognitive testing (1999–2002) were genotyped. We used linear models adjusting for first degree relationships via generalized estimating equations (GEE) and family based association tests (FBAT) in additive models to relate qualifying single nucleotide polymorphisms (SNPs, 70,987 autosomal on Affymetrix 100K Human Gene Chip with minor allele frequency ≥ 0.10, genotypic call rate ≥ 0.80, and Hardy-Weinberg equilibrium p-value ≥ 0.001) to multivariable-adjusted residuals of 9 MRI measures including total cerebral brain (TCBV), lobar, ventricular and white matter hyperintensity (WMH) volumes, and 6 cognitive factors/tests assessing verbal and visuospatial memory, visual scanning and motor speed, reading, abstract reasoning and naming. We determined multipoint identity-by-descent utilizing 10,592 informative SNPs and 613 short tandem repeats and used variance component analyses to compute LOD scores.

Results

The strongest gene-phenotype association in FBAT analyses was between SORL1 (rs1131497; p = 3.2 × 10^-6) and abstract reasoning, and in GEE analyses between CDH4 (rs1970546; p = 3.7 × 10^-8) and TCBV. SORL1 plays a role in amyloid precursor protein processing and has been associated with the risk of AD. Among the 50 strongest associations (25 each by GEE and FBAT) were other biologically interesting genes. Polymorphisms within 28 of 163 candidate genes for stroke, AD and memory impairment were associated with the endophenotypes studied at p < 0.001. We confirmed our previously reported linkage of WMH on chromosome 4 and describe linkage of reading performance to a marker on chromosome 18 (GATA11A06), previously linked to dyslexia (LOD scores = 2.2 and 5.1).

Conclusion

Our results suggest that genes associated with clinical neurological disease also have detectable effects on subclinical phenotypes. These hypothesis generating data illustrate the use of an unbiased approach to discover novel pathways that may be involved in brain aging, and could be used to replicate observations made in other studies.

     

Genetic analysis of IQ,processing speed and stimulus-response incongruency effects

Psychometric IQ (WAIS-III), onset and peak latency of the lateralized readiness potential (LRP), decision time, and accuracy were assessed during an Eriksen Flanker task in a young (149 families) and in an older (122 families) cohort of twins and their siblings. Stimulus-response incongruency effects were found on all measures of processing speed and accuracy. The effects on the percentages of wrong button presses and too slow (>1,000 ms) responses were larger in the older than in the younger age cohort. Significant heritability was found for processing speed (33-48%), accuracy (41%), and stimulus-response incongruency effects (3-32%). Verbal and performance IQ correlated significantly with stimulus-response incongruency effects on accuracy (-0.22 to -0.39), and this correlation was completely mediated by an underlying set of common genes. It is concluded that measures of the ability to perform well under conditions of stimulus-response incongruency are viable endophenotypes of cognitive ability.     

Differences in Resting EEG Related to Ability

The aim of the present study was to investigate the relationship between different EEG measures (mean power, mean frequency, approximated entropy and coherence), and ability (creativity and intelligence). For that purpose the EEG of 115 student-teachers (Intelligence: Creativity - standardized scores: was recorded while they were resting with eyes open and closed. The study showed only weak correlations between measures based on the level of activity in different areas (mean power, mean frequency and approximated entropy) and creativity. The correlations with IQ scores were even less pronounced. On the other hand, coherence measures showed a much more intense relationship both with creativity as well as with intelligence. In the eyes-open state these differences were mainly distributed over the right hemisphere. The results are discussed in the light of different theories relating brain functioning and ability.     

Germ-Line chromosomal localization of genes in chromosome 11p linkage: Parathyroid hormone, β-globin,c-Ha-ras-1, and insulin

The chromosomal localization of genes for parathyroid hormone (PTH), -globin cluster, c-Ha-ras-1, and insulin, all of which have previously been assigned to the short arm of chromosome 11, generated considerable interest because of their association with development of disease states. Furthermore, the availability of recombination data from family studies made the determination of their physical location on the chromosome necessary. Several investigators have attempted this; however, controversy has arisen concerning the location of -globin, insulin, and c-Ha-ras-1 genes. Thus, while the results of some investigators suggested that all three genes are situated in the 11 p15 region, data of other investigators placed the -globin and insulin genes close to the centromere and c-Ha-ras-1 in a more proximal region than 11p15. The subchromosomal position of the PTH gene remains to be determined. We have performed in situ hybridization of meiotic pachytene bivalents with³H-labeled cloned genomic probes of PTH, -globin, and insulin genes and find their germ-line positions to be the following: PTH at 11p11.21, -globin at 11p11.22, and insulin at 11p14.1. These data, when considered with our recent germ-line assignment of the c-Ha-ras-1 gene to 11p14.1, indicate the following relative order on 11p: cen-PTH--globin-c-Ha-ras-insulin or cen-PTH--globin-insulin-c-Ha-ras. The former order is consistent with genetic evidence from linkage analysis of DNA polymorphisms adjacent to these genes segregating in families.     

Brain white matter damage in aging and cognitive ability in youth and older age

Cerebral white matter hyperintensities (WMH) reflect accumulating white matter damage with aging and impair cognition. The role of childhood intelligence is rarely considered in associations between cognitive impairment and WMH. We studied community-dwelling older people all born in 1936, in whom IQ had been assessed at age 11 years. We assessed medical histories, current cognitive ability and quantified WMH on MR imaging. Among 634 participants, mean age 72.7 (SD 0.7), age 11 IQ was the strongest predictor of late life cognitive ability. After accounting for age 11 IQ, greater WMH load was significantly associated with lower late life general cognitive ability (β = ?0.14, p < 0.01) and processing speed (β = ?0.19, p < 0.001). WMH were also associated independently with lower age 11 IQ (β = ?0.08, p < 0.05) and hypertension. In conclusion, having more WMH is significantly associated with lower cognitive ability, after accounting for prior ability, age 11IQ. Early-life IQ also influenced WMH in later life. Determining how lower IQ in youth leads to increasing brain damage with aging is important for future successful cognitive aging.     

Cognitive and behavioral phenotype of children with pseudohypoparathyroidism type 1A

Pseudohypoparathyroidism 1A (PHP1A) is a rare, genetic disorder. Most patients with PHP1A have cognitive impairment but this has not been systematically studied. We hypothesized that children with PHP1A would have lower intelligent quotient (IQ) scores than controls. To evaluate cognition and behavior, we prospectively enrolled children with PHP1A, one unaffected sibling (when available) and controls matched on BMI/age/gender/race. Evaluations included cognitive and executive function testing. Parents completed questionnaires on behavior and executive function. We enrolled 16 patients with PHP1A, 8 unaffected siblings, and 15 controls. Results are presented as mean (SD). The PHP1A group had a composite IQ of 85.9 (17.2); 25% had a composite IQ < ?2 SD. The PHP1A group had significantly lower IQs than matched controls (composite IQ ?17.3, 95%CI ?28.1 to ?6.5, p < 0.01) and unaffected siblings (composite IQ ?21.5, 95%CI ?33.9 to ?9.1, p < 0.01). Special education services were utilized for 93% of the patients with PHP1A. Deficits were observed in executive function and parents reported delayed adaptive behavior skills and increased rates of attention deficit hyperactivity disorder. In conclusion, children with PHP1A have lower intelligence quotient scores, poorer executive function, delayed adaptive behavior skills, and increased behavior problems.

     

The ongoing adaptive evolution of ASPM and Microcephalin is not explained by increased intelligence

Recent studies have made great strides towards identifying putative genetic events underlying the evolution of the human brain and its emergent cognitive capacities. One of the most intriguing findings is the recurrent identification of adaptive evolution in genes associated with primary microcephaly, a developmental disorder characterized by severe reduction in brain size and intelligence, reminiscent of the early hominid condition. This has led to the hypothesis that the adaptive evolution of these genes has contributed to the emergence of modern human cognition. As with other candidate loci, however, this hypothesis remains speculative due to the current lack of methodologies for characterizing the evolutionary function of these genes in humans. Two primary microcephaly genes, ASPM and Microcephalin, have been implicated not only in the adaptive evolution of the lineage leading to humans, but in ongoing selective sweeps in modern humans as well. The presence of both the putatively adaptive and neutral alleles at these loci provides a unique opportunity for using normal trait variation within humans to test the hypothesis that the recent selective sweeps are driven by an advantage in cognitive abilities. Here, we report a large-scale association study between the adaptive alleles of these genes and normal variation in several measures of IQ. Five independent samples were used, totaling 2393 subjects, including both family-based and population-based datasets. Our overall findings do not support a detectable association between the recent adaptive evolution of either ASPM or Microcephalin and changes in IQ. As we enter the post-genomic era, with the number of candidate loci underlying human evolution growing rapidly, our findings highlight the importance of direct experimental validation in elucidating their evolutionary role in shaping the human phenotype.     

A study on the correlation between IL1RAPL1 and human cognitive ability

This study aimed to investigate the effects of IL1RAPL1 on the human cognitive ability. Four genetic marker sites, i.e., DXS1218, DXS9896, rs6526806 and rs12847959 on IL1RAPL1 were genotyped in 332 Qinba Mountain Area children. Meanwhile, a cognition test with a C-WISC scale was performed to study the relationship of genotype with cognition test scores. Results indicated that genotypes of DXS1218, DXS9896 and rs12847959 were associated with memory/concentration factor intelligence quotient (IQ) (P=0.027, 0.042, 0.029, respectively). DXS1218 also associated with full IQ, verbal IQ, and performance IQ (P=0.006, 0.014, 0.006, respectively). rs12847959 were related to verbal comprehension factor and perceptual organization factor IQ (P=0.021, 0.043, respectively). Further study on rat brain revealed that Il1rapl was mainly expressed in memory/concentration-associated encephalic regions, such as hippocampus, dentate fascia, osmesis perithelium, and piriform cortex. mRNA expression levels of Il1rapl in brains of rats with different learning and memory abilities showed significant difference. Combined data suggested that IL1RAPL1 affected human cognitive ability to some extent, especially the memory and concentration capability.     

Association Study of Common Mitochondrial Variants and Cognitive Ability

Mitochondria are central to optimal functioning of the nervous system and disruption of mitochondrial function is known to lead to cognitive impairment. However, there has been little focus on whether common mitochondrial DNA polymorphisms contribute to normal variation in cognitive phenotypes. In this study, we use methodology for carrying out whole mitochondrial association studies in family cohorts to test whether 69 common mitochondrial variants and 10 common European haplogroups are associated with a number of measures of cognition, including information processing, word recognition and general cognitive ability, in a sample of Australian adolescent twins and their singleton/non-twin siblings. With data from 1,385 individuals from 665 families, this is by far the largest mitochondrial association study of cognition undertaken to date. We find that there is no significant evidence that either common European mitochondrial SNPs or haplogroups are associated with variation in cognitive performance. In spite of the associations not reaching significance, several of the most highly associated SNPs are in mitochondrial genes that have previously been identified as potentially playing a role in cognitive performance in mice. These genes warrant further investigation in both functional and association studies with larger cohorts. Edited by Chandra Reynolds.     

Common genetic variation and performance on standardized cognitive tests

One surprising feature of the recently completed waves of genome-wide association studies is the limited impact of common genetic variation in individually detectable polymorphisms on many human traits. This has been particularly pronounced for studies on psychiatric conditions, which have failed to produce clear, replicable associations for common variants. One popular explanation for these negative findings is that many of these traits may be genetically heterogeneous, leading to the idea that relevant endophenotypes may be more genetically tractable. Aspects of cognition may be the most important endophenotypes for psychiatric conditions such as schizophrenia, leading many researchers to pursue large-scale studies on the genetic contributors of cognitive performance in the normal population as a surrogate for aspects of liability to disease. Here, we perform a genome-wide association study with two tests of executive function, Digit Symbol and Stroop Color-Word, in 1086 healthy volunteers and with an expanded cognitive battery in 514 of these volunteers. We show that, consistent with published studies of the psychiatric conditions themselves, no single common variant has a large effect (explaining >4–8% of the population variation) on the performance of healthy individuals on standardized cognitive tests. Given that these are important endophenotypes, our work is consistent with the idea that identifying rare genetic causes of psychiatric conditions may be more important for future research than identifying genetically homogenous endophenotypes.     

Age at natural menopause and cognition

OBJECTIVES: To examine associations between age at natural menopause, childhood IQ and cognition at age 65 years. To determine if lower age at menopause partly mediates the effect of childhood IQ on cognition at age 65 years. METHODS: Data were provided by a sub-cohort of women participating in a longitudinal study of brain ageing and health. Main variables were childhood IQ from a 1947 national survey of children born in 1936, age at natural menopause and five cognitive tests measured in 2000-2001. RESULTS: Age at menopause was associated with childhood IQ (r = 0.221, P = 0.008) and with general cognitive function age 65 years (r = 0.246, P = 0.004). Multiple regression showed 44.4% of the reliable variance in cognitive ability age 65 years is contributed by IQ at an age of 11 years to which, years of education contributed an additional 3.9%. Structural equation modelling suggested that childhood IQ differences contribute 4.8% of the variance to age at natural menopause and that the relation between age at menopause and cognition at age 65 years was accounted for by childhood IQ. CONCLUSION: Childhood IQ and age at menopause each have significant relations with general cognitive function age 65 years but the link between cognition age 65 years and age at menopause might be wholly explained by childhood IQ. The association between childhood IQ and age at menopause may be attributed to central neural mechanisms or, as argued here, to the effects of childhood IQ on adult general health.     

Cognition and social cognition in non-psychotic siblings of patients with schizophrenia

Introduction. Deficits in Social Cognition are common in people with schizophrenia. However, it is not clear if these deficits are a vulnerability marker and whether they are independent to cognitive difficulties. This study investigates these two issues in individuals with a genetic liability to psychosis.

Methods. Twenty-one healthy siblings of patients with schizophrenia were compared with 21 healthy individuals on a range of cognitive and social cognitive measures. Significant differences in cognitive domains were controlled for when comparing the two groups on measures of social cognition.

Results. Siblings of people with schizophrenia performed significantly worst on tests of theory of mind and social perception but not on affect recognition. Scores on tests of executive function, processing speed and general IQ were also lower in the sibling group. When controlled for differences in cognitive tests, the two groups still retained significant differences in theory of mind and social perception. However, executive function significantly contributed to theory of mind and processing speed to social perception differences.

Conclusions. These results further suggest that difficulties in some domains of social cognition are associated with a genetic vulnerability for schizophrenia. In these areas, cognitive difficulties account only partially for social cognition problems suggesting that these two domains may represent relatively independent liability factors.     

Perceptual Speed and IQ Are Associated Through Common Genetic Factors

Individual differences in inspection time explain about 20% of IQ test variance. To determine whether the association between inspection time and IQ is mediated by common genes or by a common environmental factor, inspection time and IQ were assessed in an extended twin design. Data from 688 participants from 271 families were collected as part of a large ongoing project on the genetics of adult brain function and cognition. The sample consisted of a young adult cohort (mean age 26.2 years) and an older adult cohort (mean age 50.4 years). IQ was assessed with the Dutch version of the WAIS-3R. Inspection time was measured in the so-called -paradigm, in which a subject is asked to decide which leg of the -figure is longest at varying display times of the -figure. The number of correct inspections per second (i.e., the reciprocal of inspection time) was used to index perceptual speed. For Verbal IQ and Performance IQ, heritabilities were 85% and 69%, respectively. For perceptual speed, 46% of the total variance was explained by genetic variance. No differences in heritability estimates across age cohorts or sexes were found. Across the whole sample, a significant phenotypic correlation was found between perceptual speed and Verbal IQ (0.19) and between perceptual speed and Performance IQ (0.27). These correlations were entirely due to a common genetic factor that accounted for 10% of the genetic variance in verbal IQ and for 22% of the genetic variance in performance IQ. This factor is hypothesized to reflect the influence of genetic factors that determine axonal myelination in the central nervous system.     

A Functional Polymorphism under Positive Evolutionary Selection in ADRB2 is Associated with Human Intelligence with Opposite Effects in the Young and the Elderly

Comparative genomics offers a novel approach to unravel the genetic basis of complex traits. We performed a two stage analysis where genes ascertained for enhanced protein evolution in primates are subsequently searched for the presence of non-synonymous coding SNPs in the current human population at amino acid sites that differ between humans and chimpanzee. Positively selected genes among primates are generally presumed to determine phenotypic differences between humans and chimpanzee, such as the enhanced cognitive ability of our species. Amino acid substitutions segregating in humans at positively selected amino acid sites are expected to affect phenotypic differences among humans. Therefore we conducted an association study in two family based cohorts and one population based cohort between cognitive ability and the most likely candidate gene among the five that harbored more than one such polymorphism. The derived, human-specific allele of the beta-2 adrenergic receptor Arg16Gly polymorphism was found to be the increaser allele for performance IQ in the young, family based cohort but the decreaser allele for two different measures of cognition in the large Scottish cohort of unrelated individuals. The polymorphism is known to affect signaling activity and modulation of beta-2 adrenergic signaling has been shown to adjust memory consolidation, a trait related to cognition. The opposite effect of the polymorphism on cognition in the two age classes observed in the different cohorts resembles the effect of ADRB2 on hypertension, which also has been reported to be age dependent. This result illustrates the relevance of comparative genomics to detect genes that are involved in human behavior. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. Edited by Tatiana Foroud.     

Covariation between intelligence and speed of cognitive processing: Genetic and environmental influences

This study is the first analysis of the etiology of the relationship between general intelligence and speed of cognitive processing. The genetic and environmental sources of this covariation were examined using data from 60 pairs of twins (30 monozygotic and 30 same-sexed dizygotic), ages 8–18. Full-Scale IQ scores on the Wechsler Intelligence Scale for Children-Revised (WISC-R) served as an index of general intelligence. Measures of speed of processing employed were the Rapid Automatic Naming tests and Colorado Perceptual Speed tests. Results of multivariate biometrical genetic analyses revealed the importance of genetic influences underlying the IQ/speed association. The relative importance of correlated genetic effects, however, appeared to be dependent upon the specific speed-of-processing measure. Our results indicate that the phenotypic relationship between the measures of general intelligence and the measures of speed of processing employed are due largely to correlated genetic effects. While correlated specific environmental effects were less important, correlated common environmental effects were negligible. In general, the findings support the notion of some common biological mechanism(s) underlying both general intelligence and speed-of-processing measures.     

Effects of SCA1, MJD, and DPRLA triplet repeat polymorphisms on cognitive phenotypes in a normal population of adolescent twins.

The expansion of unstable trinucleotide CAG repeat polymorphisms of a number of genes causes several neurodegenerative disorders with decreased cognitive function, the severity of the disorder being related to allele length at the triplet repeat locus. While the effects of repeat length have been well studied in clinical samples, there has been little investigation of the effects of triplet repeat variation in the normal range for these genes. We have, therefore, examined linkage and association for three CAG triplet repeat markers (Spinocerebellar Ataxia Type 1, SCA1; Machado-Joseph Disease, MJD; Dentatorubro-pallidoluysian Atrophy, DRPLA) to assess their contribution to variation in cognitive ability (IQ, reading ability, processing speed) in a normal, unselected sample of adolescent twins (248 dizygotic (DZ) sibling pairs, aged 16 years). Association tests, performed in Mx and QTDT, showed a consistent positive association of SCA1 with Arithmetic (P = 0.04). While association was supported between SCA1 and Cambridge reading scores and between DRPLA and inspection time, results were inconsistent across software packages. Given the number of statistical tests performed, it is unlikely that trinucleotide repeat variation in the normal range for these genes influences variation in normal cognition.     

DNA markers associated with high versus low IQ: The IQ quantitative trait loci (QTL) project

General cognitive ability (intelligence, often indexed by IQ scores) is one of the most highly heritable behavioral dimensions. In an attempt to identify some of the many genes (quantitative trait loci; QTL) responsible for the substantial heritability of this quantitative trait, the IQ QTL Project uses an allelic association strategy. Allelic frequencies are compared for the high and low extremes of the IQ dimension using DNA markers in or near genes that are likely to be relevant to neural functioning. Permanent cell lines have been established for low-IQ (mean IQ=82;N=18), middle-IQ (mean IQ=105;N=21), and high-IQ (mean IQ=130;N=24) groups and for a replication sample consisting of even more extreme low-IQ (mean IQ=59;N=17) and high-IQ (mean IQ=142;N=27) groups. Subjects are Caucasian children tested from 6 to 12 years of age. This first report of the IQ QTL Project presents allelic association results for 46 two-allele markers and for 26 comparisons for 14 multiple-allele markers. Two markers yielded significant (p<.01) allelic frequency differences between the high- and the low-IQ groups in the combined sample—a new HLA marker for a gene unique to the human species and a new brain-expressed triplet repeat marker (CTGB33). The prospects for harnessing the power of molecular genetic techniques to identify QTL for quantitative dimensions of human behavior are discussed.     

Cognitive functioning in children with sickle cell disease: a meta-analysis

OBJECTIVE: To establish whether sickle cell disease (SCD) affects cognitive functioning in children with no evidence of cerebral infarction. METHODS: We conducted a meta-analysis of studies of cognition in SCD to determine the size of any statistical difference between children with SCD and controls. Methodological factors were evaluated according to the size and frequency of group differences. RESULTS: There were small but reliable decrements in cognitive functioning on IQ measures (4.3-point difference overall). The most methodologically rigorous studies showed a highly similar pattern. Sampling issues associated with the effect size for IQ were identified. Measures of specific abilities appear more sensitive than IQ scores to cognitive decrements in SCD. CONCLUSIONS: SCD is associated with cognitive effects even in the absence of cerebral infarction. The causes of this cognitive decrement may include direct effects of SCD on brain function or indirect effects of chronic illness.