M. Horan

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 549u2009692 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.

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 (Pu2003=u20030.001), delayed recall (Pu2003=u20030.037) and general intelligence (g) (Pu2003=u20030.008). 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.

Common SNPs explain some of the variation in the personality dimensions of neuroticism and extraversion

The personality traits of neuroticism and extraversion are predictive of a number of social and behavioural outcomes and psychiatric disorders. Twin and family studies have reported moderate heritability estimates for both traits. Few associations have been reported between genetic variants and neuroticism/extraversion, but hardly any have been replicated. Moreover, the ones that have been replicated explain only a small proportion of the heritability (<∼2%). Using genome-wide single-nucleotide polymorphism (SNP) data from ∼12u2009000 unrelated individuals we estimated the proportion of phenotypic variance explained by variants in linkage disequilibrium with common SNPs as 0.06 (s.e.=0.03) for neuroticism and 0.12 (s.e.=0.03) for extraversion. In an additional series of analyses in a family-based sample, we show that while for both traits ∼45% of the phenotypic variance can be explained by pedigree data (that is, expected genetic similarity) one third of this can be explained by SNP data (that is, realized genetic similarity). A part of the so-called ‘missing heritability’ has now been accounted for, but some of the reported heritability is still unexplained. Possible explanations for the remaining missing heritability are that: (i) rare variants that are not captured by common SNPs on current genotype platforms make a major contribution; and/ or (ii) the estimates of narrow sense heritability from twin and family studies are biased upwards, for example, by not properly accounting for nonadditive genetic factors and/or (common) environmental factors.

Prevalence and symptom profiling of oropharyngeal dysphagia in a community dwelling of an elderly population: a self‐reporting questionnaire survey

Symptomatic dysphagia is believed to be more common in the older population; however, the factors that predict age-related dysphagia are less well-understood. Here, we describe a questionnaire-based survey of swallowing dysfunction in a large, otherwise healthy community dwelling older population in the UK in whom additional cognitive and depression related scores were evaluated. A postal survey using Sydney oropharyngeal dysphagia questionnaire was sent to 800 residences in the North of England that formed part of the University of Manchester Age and Cognitive Performance Longitudinal Study. This cohort was composed of older individuals (mean age 81 [range 69-98 years]) who are otherwise healthy with no history of previous neurological disease. The postal questionnaire is a validated self-report inventory measuring symptoms of oropharyngeal dysphagia covering a total of 17 domains of swallowing function. The maximal score obtainable is 1700, with a score of ≥200 arbitrarily considered to indicate swallowing difficulty. Cognitive performance and depression scores utilized the telephone interview cognitive screen and the Geriatric Depression Scale. All data were analyzed in SPSS. Of the 800 questionnaires sent out, 637 where returned. Three were later discarded as unusable after follow-up telephone interviews of incomplete forms, giving a completed response rate of 79%. Females made up 77% of the total respondents. Of the population, 11.4% reported symptoms indicative of significant dysphagia. Unsurprisingly, dysphagia severity was directly correlated with subject age (r= 0.11, P= 0.007). When cognitive factors were taken into account, there was no correlation between memory, recall, and mental performance and dysphagia; however, depression was strongly and independently associated (P= 0.002) with dysphagia symptoms. Dysphagia symptoms are prevalent in older people, affecting nearly one in nine people who are otherwise living independently in the community. While cognitive factors such as memory recall do not seem to influence dysphagia symptoms, depression is associated with dysphagia, suggesting a potential interaction. This could relate to associations with quality of life or psychological factors.

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.

A genome-wide association study implicates the APOE locus in nonpathological cognitive ageing

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality of life and loss of independence in old age. We investigated the genetic contribution to individual differences in nonpathological cognitive ageing in five cohorts of older adults. We undertook a genome-wide association analysis using 549u2009692 single-nucleotide polymorphisms (SNPs) in 3511 unrelated adults in the Cognitive Ageing Genetics in England and Scotland (CAGES) project. These individuals have detailed longitudinal cognitive data from which phenotypes measuring each individual’s cognitive changes were constructed. One SNP—rs2075650, located in TOMM40 (translocase of the outer mitochondrial membrane 40 homolog)—had a genome-wide significant association with cognitive ageing (P=2.5 × 10−8). This result was replicated in a meta-analysis of three independent Swedish cohorts (P=2.41 × 10−6). An Apolipoprotein E (APOE) haplotype (adjacent to TOMM40), previously associated with cognitive ageing, had a significant effect on cognitive ageing in the CAGES sample (P=2.18 × 10−8; females, P=1.66 × 10−11; males, P=0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P=3.66 × 10−11) and TOMM40 (rs11556505; P=2.45 × 10−8) as loci that were associated with cognitive ageing. Imputation and conditional analyses in the discovery and replication cohorts strongly suggest that this effect is due to APOE (rs429358). Functional genomic analysis indicated that SNPs in the TOMM40/APOE region have a functional, regulatory non-protein-coding effect. The APOE region is significantly associated with nonpathological cognitive ageing. The identity and mechanism of one or multiple causal variants remain unclear.

The University of Manchester longitudinal study of cognition in normal healthy old age, 1983 through 2003.

This paper describes the participants, design, method and tests used during a 20-year longitudinal study of cognitive changes in increasing age experienced by 6542 healthy residents of Greater Manchester and Newcastle-upon-Tyne, then aged from 42 to 92 years. Information collected and updated includes demographics and health, scores on two, biennially alternated batteries of cognitive tests, repeated administrations of the Beck and Yesavage depression inventories and of self-reports of stressful life events, self-evaluation and locus of control questionnaires and detailed information on lifestyle, hobbies and occupations, physical and social activities, family circumstances and health history. Records have allowed investigation of rates of cognitive changes from 36 months to 20 years preceding death from a variety of causes. Collection of blood and saliva provide, blood chemistry and cortisol levels to analyse associations of rates of cognitive change to genetic factors, blood chemistry and cortisol levels. A random effects analysis confirms marked effects of drop-out and practice due to repeated testing and shows how true rates of change, and of increases in variability between individuals may be ascertained after these have been identified.

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.

White matter lesions account for all age-related declines in speed but not in intelligence.

MRI scans measured white matter lesion prevalence (WMLP) in 65 people ages 65-84 years who also took 17 cognitive tests: 3 tests of general fluid intelligence, 3 of vocabulary, 2 of episodic and 3 of working memory, 2 of processing speed, and 4 of frontal and executive function. Entry of age with WMLP into regression equations as predictors of test scores showed that inferences about the functional relationships between markers of brain aging and cognitive impairments are seriously misleading if they are based on simple correlations alone. A new finding that WMLP accounts for all of the age-related variance between individuals in tests of speed and executive ability but for none of the age-related variance in intelligence revises current hypotheses that gross brain changes affect general fluid intelligence and other mental abilities solely through their effects on information-processing speed.

Fear of falling more important than pain and depression for functional recovery after surgery for hip fracture in older people.

BACKGROUNDnDepression and cognitive functioning have a negative impact on functional recovery after hip fracture surgery in older people, and the same has been suggested for pain and fear of falling. These variables, however, have never been studied together, nor has the timing of psychiatric assessment been taken into account.nnnMETHODnTwo parallel, randomized controlled trials were undertaken aiming to prevent and treat depression after hip fracture surgery in older people. Multiple logistic regression analyses corrected for age and pre-morbid level of functioning were performed to evaluate the effect of depressive symptoms (15-item Geriatric Depression Scale, GDS), pain (Wong-Baker pain scale), cognitive functioning (Mini-mental State Examination, MMSE) and fear of falling (Modified Falls Efficacy Scale, MFES) within 2 weeks after surgery and 6 weeks later on functional recovery at 6 months. Main outcome measures were performance-based measures (up-and-go test, gait test, functional reach) and the self-report Sickness Impact Profile (SIP) questionnaire to assess the impact of the hip fracture on activities of daily living (ADL).nnnRESULTSnTwo hundred and ninety-one patients participated and outcome measures for 187 (64%) patients were available at 6 months. All mental health variables interfered with functional recovery. However, in the final multivariate model, cognitive functioning and fear of falling assessed 6 weeks after surgery consistently predicted functional recovery, whereas pain and depressive symptoms were no longer significant.nnnCONCLUSIONnFear of falling and cognitive functioning may be more important than pain and depression to predict functional recovery after hip fracture surgery. Rehabilitation strategies should take this into account.