A genetic association analysis of cognitive ability and cognitive ageing using 325 markers for 109 genes associated with oxidative stress or cognition

Background

Non-pathological cognitive ageing is a distressing condition affecting an increasing number of people in our 'ageing society'. Oxidative stress is hypothesised to have a major role in cellular ageing, including brain ageing.

Results

Associations between cognitive ageing and 325 single nucleotide polymorphisms (SNPs), located in 109 genes implicated in oxidative stress and/or cognition, were examined in a unique cohort of relatively healthy older people, on whom we have cognitive ability scores at ages 11 and 79 years (LBC1921). SNPs showing a significant positive association were then genotyped in a second cohort for whom we have cognitive ability scores at the ages of 11 and 64 years (ABC1936). An intronic SNP in the APP gene (rs2830102) was significantly associated with cognitive ageing in both LBC1921 and a combined LBC1921/ABC1936 analysis (p < 0.01), but not in ABC1936 alone.

Conclusion

This study suggests a possible role for APP in normal cognitive ageing, in addition to its role in Alzheimer's disease.     

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.     

Evidence for statistical epistasis between catechol-<Emphasis Type="Italic">O</Emphasis>-methyltransferase (COMT) and polymorphisms in RGS4, G72 (DAOA), GRM3, and DISC1: influence on risk of schizophrenia

Catechol-O-methyltransferase (COMT) regulates dopamine degradation and is located in a genomic region that is deleted in a syndrome associated with psychosis, making it a promising candidate gene for schizophrenia. COMT also has been shown to influence prefrontal cortex processing efficiency. Prefrontal processing dysfunction is a common finding in schizophrenia, and a background of inefficient processing may modulate the effect of other candidate genes. Using the NIMH sibling study (SS), a non-independent case-control set, and an independent German (G) case-control set, we performed conditional/unconditional logistic regression to test for epistasis between SNPs in COMT (rs2097603, Val158Met (rs4680), rs165599) and polymorphisms in other schizophrenia susceptibility genes. Evidence for interaction was evaluated using a likelihood ratio test (LRT) between nested models. SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. A striking result was found in RGS4: three of five SNPs showed a significant increase in risk [LRT P-values: 90387 = 0.05 (SS); SNP4 = 0.02 (SS), 0.02 (G); SNP18 = 0.04 (SS), 0.008 (G)] in interaction with COMT; main effects for RGS4 SNPs were null. Significant results for SNP4 and SNP18 were also found in the German study. We were able to detect statistical interaction between COMT and polymorphisms in candidate genes for schizophrenia, many of which had no significant main effect. In addition, we were able to replicate other studies, including allelic directionality. The use of epistatic models may improve replication of psychiatric candidate gene studies.     

Retinal Vascular Fractal Dimension,Childhood IQ,and Cognitive Ability in Old Age: The Lothian Birth Cohort Study 1936

Purpose

Cerebral microvascular disease is associated with dementia. Differences in the topography of the retinal vascular network may be a marker for cerebrovascular disease. The association between cerebral microvascular state and non-pathological cognitive ageing is less clear, particularly because studies are rarely able to adjust for pre-morbid cognitive ability level. We measured retinal vascular fractal dimension (D _f) as a potential marker of cerebral microvascular disease. We examined the extent to which it contributes to differences in non-pathological cognitive ability in old age, after adjusting for childhood mental ability.

Methods

Participants from the Lothian Birth Cohort 1936 Study (LBC1936) had cognitive ability assessments and retinal photographs taken of both eyes aged around 73 years (n = 648). IQ scores were available from childhood. Retinal vascular D _f was calculated with monofractal and multifractal analysis, performed on custom-written software. Multiple regression models were applied to determine associations between retinal vascular D _f and general cognitive ability (g), processing speed, and memory.

Results

Only three out of 24 comparisons (two eyes × four D _f parameters × three cognitive measures) were found to be significant. This is little more than would be expected by chance. No single association was verified by an equivalent association in the contralateral eye.

Conclusions

The results show little evidence that fractal measures of retinal vascular differences are associated with non-pathological cognitive ageing.     

The molecular genetics of cognition: dopamine, COMT and BDNF

The important contribution of genetic factors to the development of cognition and intelligence is widely acknowledged, but identification of these genes has proven to be difficult. Given a variety of evidence implicating the prefrontal cortex and its dopaminergic circuits in cognition, most of the research conducted to date has focused on genes regulating dopaminergic function. Here we review the genetic association studies carried out on catechol-O-methyltransferase (COMT) and the dopamine receptor genes, D1, D2 and D4. In addition, the evidence implicating another promising candidate gene, brain-derived neurotrophic factor (BDNF) in neuropsychological function, is assessed. Both the COMT val158met polymorphism and the BDNF val66met variant appear to influence cognitive function, but the specific neurocognitive processes involved continue to be a matter of debate. Part of the difficulty is distinguishing between false positives, pleiotropy and the influence of a general intelligence factor, g. Also at issue is the complexity of the relevant neuromolecular pathways, which make the inference of simple causal relationships difficult. The implications of molecular genetic cognitive research for psychiatry are discussed in light of these data.     

Investigating the Genetic Basis of Theory of Mind (ToM): The Role of Catechol-O-Methyltransferase (COMT) Gene Polymorphisms

The ability to deduce other persons'' mental states and emotions which has been termed ‘theory of mind (ToM)’ is highly heritable. First molecular genetic studies focused on some dopamine-related genes, while the genetic basis underlying different components of ToM (affective ToM and cognitive ToM) remain unknown. The current study tested 7 candidate polymorphisms (rs4680, rs4633, rs2020917, rs2239393, rs737865, rs174699 and rs59938883) on the catechol-O-methyltransferase (COMT) gene. We investigated how these polymorphisms relate to different components of ToM. 101 adults participated in our study; all were genetically unrelated, non-clinical and healthy Chinese subjects. Different ToM tasks were applied to detect their theory of mind ability. The results showed that the COMT gene rs2020917 and rs737865 SNPs were associated with cognitive ToM performance, while the COMT gene rs5993883 SNP was related to affective ToM, in which a significant gender-genotype interaction was found (p = 0.039). Our results highlighted the contribution of DA-related COMT gene on ToM performance. Moreover, we found out that the different SNP at the same gene relates to the discriminative aspect of ToM. Our research provides some preliminary evidence to the genetic basis of theory of mind which still awaits further studies.     

Diverse facets of COMT: from a plausible predictive marker to a potential drug target for schizophrenia

Dopaminergic system in the prefrontal cortex (PFC) is known to regulate the cognitive functions. Catechol-O-methyl transferase (COMT), one of the major modulators of prefrontal dopamine function, has emerged as an important determinant of schizophrenia associated cognitive dysfunction and response to antipsychotics. A common Val->Met polymorphism (rs4680) in the COMT gene, associated with increased prefrontal dopamine catabolism, impairs prefrontal cognition and might increase risk for schizophrenia. Further, the degree of cognitive improvement observed with antipsychotics in schizophrenia patients is influenced by the COMT activity, and Val/Met has been proposed as a potential pharmacogenetic marker. However, studies evaluating the role of COMT have been equivocal. The presence of other functional polymorphisms in the gene, and the observed ethnic variations in the linkage disequilibrium structure at COMT locus, suggest that COMT activity regulation might be complex. Despite these lacunae in our current understanding, the influence of COMT on PFC mediated cognitive tasks is undeniable. COMT thus represents an attractive candidate for novel therapeutic interventions for cognitive dysfunction. The COMT activity inhibiting drugs including tolcapone and entacapone, have shown promising potential as they selectively modulate dopaminergic transmission. This review is an attempt to summarize the rapidly evolving literature exploring the diverse facets of COMT biology, its functional relevance as a predictive marker and a therapeutic target for schizophrenia.     

Genome-wide quantitative trait locus association scan of general cognitive ability using pooled DNA and 500K single nucleotide polymorphism microarrays

General cognitive ability ( g ), which refers to what cognitive abilities have in common, is an important target for molecular genetic research because multivariate quantitative genetic analyses have shown that the same set of genes affects diverse cognitive abilities as well as learning disabilities. In this first autosomal genome-wide association scan of g , we used a two-stage quantitative trait locus (QTL) design with pooled DNA to screen more than 500 000 single nucleotide polymorphisms (SNPs) on microarrays, selecting from a sample of 7000 7-year-old children. In stage 1, we screened for allele frequency differences between groups pooled for low and high g . In stage 2, 47 SNPs nominated in stage 1 were tested by individually genotyping an independent sample of 3195 individuals, representative of the entire distribution of g scores in the full 7000 7-year-old children. Six SNPs yielded significant associations across the normal distribution of g , although only one SNP remained significant after a false discovery rate of 0.05 was imposed. However, none of these SNPs accounted for more than 0.4% of the variance of g , despite 95% power to detect associations of that size. It is likely that QTL effect sizes, even for highly heritable traits such as cognitive abilities and disabilities, are much smaller than previously assumed. Nonetheless, an aggregated 'SNP set' of the six SNPs correlated 0.11 ( P  < 0.00000003) with g . This shows that future SNP sets that will incorporate many more SNPs could be useful for predicting genetic risk and for investigating functional systems of effects from genes to brain to behavior.     

Investigating cognitive genetics and its implications for the treatment of cognitive deficit

Cognitive impairment in the elderly, caused by either normal ageing process or dementia, is an increasing problem in developed countries that has enormous social and economic considerations. Research investigating the genetic basis of cognition is a new and rapidly developing field that may aid in the development of new treatments for age-related cognitive deficit. Over the past 6 years, a number of quantitative trait loci (QTLs) have been associated with cognitive functioning in humans including loci within the genes catechol- o -methyltransferase, brain-derived neurotrophic factor, muscle segment homeobox 1, serotonin transporter 2A (HTR2A), cholinergic muscarinic receptor 2, cathepsin D, metabotrophic glutamate receptor and most recently the class II human leukocyte antigens. Unfortunately, inconsistency within the literature, which is a hallmark of almost all association studies investigating complex diseases and traits, is casting doubt as to which genes are truly associated with cognition and which are a result of Type 2 error. This review will highlight implicated intelligence QTLs, examine the probable reasons for the current discrepancies between reports and discuss the potential advantages that may be procured from the study of cognitive genetics.     

COMT Val158Met and cognition: main effects and interaction with educational attainment

Studies in children have shown that the genetic influence on cognition is positively correlated with socioeconomic status. Catechol- O -methyltransferase (COMT) Val158Met, a common, functional polymorphism, has been implicated in executive cognition and working memory. Imaging studies have shown that the variant Met allele is associated with more efficient prefrontal cortical processing and better attention but also emotional vulnerability to stress. We hypothesized that COMT Val158Met genotype would interact with years of education (yrs ed), one indicator of socioeconomic adversity, to predict cognitive task performance. We therefore administered the Wechsler Adult Intelligence Scale-Revised (WAIS-R) to 328 community-derived, genotyped, Plains American Indians (mean yrs ed = 12; range = 5–18). We found significant genotypic effects on WAIS-R measures of long-term memory, working memory and attention. The Met allele was associated with improved performance in the Information and Picture Completion subscales; Met/Met homozygotes performed the best. COMT genotype interacted with yrs ed to influence Information and Block Design scores: Met allele carriers' scores improved markedly with increasing yrs ed, whereas the scores of Val/Val individuals were only marginally influenced by yrs ed. There was a crossover of effects at 11–12 yrs ed: in the less educated group, Met allele carriers actually performed worse than Val/Val individuals perhaps because of emotional vulnerability to educational adversity, but in the better educated group, Met allele carriers excelled. Our study in Plains American Indians has shown that COMT Val158Met influences several aspects of cognition and some of its effects are moderated by educational adversity.     

Associations between polymorphisms in five inflammation‐related genes and cognitive ability in older persons

Several studies have found associations between inflammatory biomarker levels and cognitive ability. This study tested the relationship between polymorphisms in genes that are associated with or encode the biomarkers and cognitive ability and estimated lifetime cognitive change. Data came from the aspirin for asymptomatic atherosclerosis trial (n = 2091, mean age = 67.2 years ). Twelve single nucleotide polymorphisms (SNPs) were genotyped from five genes (IL‐1α, IL‐1β, IL‐6, HNF‐1A and F13A1). Cognition was assessed via administration of a five‐test battery of psychometric tests, which were used to derive a general intelligence factor, g. A vocabulary‐based cognitive test was also administered and adjusted for in the analysis to enable an estimation of lifetime cognitive change. Age‐ and sex‐adjusted analyses yielded one weakly significant association between the IL‐1α rs2856838 SNP and a measure of mental flexibility/processing speed (P = 0.044). Adjustment for the vocabulary‐based scores resulted in a single, significant association between the IL‐1α rs3783546 SNP and a measure of processing speed (P = 0.048). There is little evidence to suggest an association between SNPs in the inflammation‐related genes IL‐1α, IL‐1β, IL‐6, TCF‐1 and F13A1 and cognition in an elderly population of community‐dwelling Scottish citizens.     

Virtual navigation in humans: the impact of age, sex, and hormones on place learning

Certain cognitive processes, including spatial ability, decline with normal aging. Spatial ability is also a cognitive domain with robust sex differences typically favoring males. However, tests of spatial ability do not seem to measure a homogeneous class of processes. For many, mentally matching rotated three-dimensional images is the gold standard for measuring spatial cognition in humans, while the Morris water task (MWT) is a preferred method in the domain of nonhuman animal research. The MWT is sensitive to hippocampal damage, a structure critical for normal learning and memory and often implicated in age-related cognitive decline. A computerized (virtual) version of the MWT (VMWT) appears to require and engage human hippocampal circuitry, and has proven useful in studying sex differences and testing spatial learning theories. In Experiment 1, we tested participants (20-90 years of age) in the VMWT and compared their performance to that on the Vandenberg Mental Rotation Test. We report an age-related deficit in performance on both tasks. In Experiment 2, we tested young (age 20-39) and elderly (age >60) participants in the VMWT and correlated their performance to the circulating levels of testosterone and cortisol. Our findings indicate that the persistence of male spatial advantage may be related to circulating testosterone, but not cortisol levels, and independent of generalized age-related cognitive decline.     

Patterns of linkage disequilibrium and association mapping in diploid alfalfa (M. sativa L.)

Association mapping enables the detection of marker-trait associations in unstructured populations by taking advantage of historical linkage disequilibrium (LD) that exists between a marker and the true causative polymorphism of the trait phenotype. Our first objective was to understand the pattern of LD decay in the diploid alfalfa genome. We used 89 highly polymorphic SSR loci in 374 unimproved diploid alfalfa (Medicago sativa L.) genotypes from 120 accessions to infer chromosome-wide patterns of LD. We also sequenced four lignin biosynthesis candidate genes (caffeoyl-CoA 3-O-methyltransferase (CCoAoMT), ferulate-5-hydroxylase (F5H), caffeic acid-O-methyltransferase (COMT), and phenylalanine amonialyase (PAL 1)) to identify single nucleotide polymorphisms (SNPs) and infer within gene estimates of LD. As the second objective of this study, we conducted association mapping for cell wall components and agronomic traits using the SSR markers and SNPs from the four candidate genes. We found very little LD among SSR markers implying limited value for genomewide association studies. In contrast, within gene LD decayed within 300 bp below an r (2) of 0.2 in three of four candidate genes. We identified one SSR and two highly significant SNPs associated with biomass yield. Based on our results, focusing association mapping on candidate gene sequences will be necessary until a dense set of genome-wide markers is available for alfalfa.     

Molecular characterization of the Rocky Mountain elk (Cervus elaphus nelsoni) PRNP putative promoter

Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy (TSE) affecting deer (Odocoileus spp.), moose (Alces alces), and Rocky Mountain elk (Cervus elaphus nelsoni). Leucine homozygosity at elk PRNP codon 132 has been associated with reduced CWD susceptibility. However, naturally acquired CWD has been detected in elk possessing the 132 Leu/Leu genotype. Recent human and bovine studies indicate that PRNP regulatory polymorphisms may also influence TSE occurrence. Therefore, we generated sequences for the elk PRNP putative promoter (2.2 kb), exon 1 (predicted; 54 bp), intron 1 (predicted; 193 bp), and exon 3 (771 bp). Promoter prediction analysis using CpGProD yielded a single elk PRNP promoter that was homologous to regions of known promoter activity in cow and sheep. Molecular interrogation of the elk PRNP putative promoter revealed 32 diallelic single-nucleotide polymorphisms (SNPs). No variation was detected within the predicted exon 1 or intron 1 sequences. Evaluation of elk PRNP exon 3 revealed 3 SNPs (63Y, 312R, 394W-->Met/Leu). Bayesian haplotype reconstruction resulted in 3 elk PRNP haplotypes, with complete linkage disequilibrium observed between all PRNP putative promoter SNPs and codon 132. The results of this study provide the initial genomic foundation for future comparative and haplotype-based elk PRNP studies.     

Characterization of a 320-kb region containing the HEXA gene on bovine chromosome 10 and analysis of its association with BSE susceptibility

Bovine spongiform encephalopathy (BSE) belongs to a group of neurodegenerative diseases known as transmissible prion diseases. Recently, variants in the promoter region of the prion protein ( PRNP ) gene have been shown to have a considerable effect on the susceptibility to BSE. However, a previous genome scan revealed other putative BSE-susceptibility loci. Here, we analysed such a region on BTA10, which contains the functional candidate gene HEXA . Three hundred and twenty kilobases that, besides HEXA , also contain ARIH1 , BRUNOL6 and PARP6 were characterized and screened for polymorphisms. Genotyping of 38 SNPs in Holstein–Friesian animals from the UK (350 diseased and 270 controls) revealed two intronic SNPs that were associated with BSE incidence, with experiment-wise P -values of 3.5 × 10⁻³ and 7.7 × 10⁻³ respectively. Both SNPs were in strong linkage disequilibrium and the rare alleles had a protective effect. These alleles were contained in a haplotype dubbed 'UK-protective' that was significantly overrepresented in the controls with a permuted P -value of 2 × 10⁻³. An association study in German Holstein animals (73 diseased and 627 controls) revealed an opposite effect of the 'UK-protective' haplotype in this population, i.e. it was overrepresented in the diseased animals, although not significant after correction for multiple testing. These findings indicate a causal variant for BSE susceptibility on BTA10 in linkage disequilibrium with the markers studied. Candidate gene analyses of the surrounding region and additional association studies will help to clarify the origin of the protective effects and to identify causal variants for BSE susceptibility on BTA10.     

Genetic Basis of a Cognitive Complexity Metric

Relational complexity (RC) is a metric reflecting capacity limitation in relational processing. It plays a crucial role in higher cognitive processes and is an endophenotype for several disorders. However, the genetic underpinnings of complex relational processing have not been investigated. Using the classical twin model, we estimated the heritability of RC and genetic overlap with intelligence (IQ), reasoning, and working memory in a twin and sibling sample aged 15-29 years (N = 787). Further, in an exploratory search for genetic loci contributing to RC, we examined associated genetic markers and genes in our Discovery sample and selected loci for replication in four independent samples (ALSPAC, LBC1936, NTR, NCNG), followed by meta-analysis (N>6500) at the single marker level. Twin modelling showed RC is highly heritable (67%), has considerable genetic overlap with IQ (59%), and is a major component of genetic covariation between reasoning and working memory (72%). At the molecular level, we found preliminary support for four single-marker loci (one in the gene DGKB), and at a gene-based level for the NPS gene, having influence on cognition. These results indicate that genetic sources influencing relational processing are a key component of the genetic architecture of broader cognitive abilities. Further, they suggest a genetic cascade, whereby genetic factors influencing capacity limitation in relational processing have a flow-on effect to more complex cognitive traits, including reasoning and working memory, and ultimately, IQ.     

Genome-wide association study identifies loci and candidate genes for meat quality traits in Simmental beef cattle

Improving meat quality is the best way to enhance profitability and strengthen competitiveness in beef industry. Identification of genetic variants that control beef quality traits can help breeders design optimal breeding programs to achieve this goal. We carried out a genome-wide association study for meat quality traits in 1141 Simmental cattle using the Illumina Bovine HD 770K SNP array to identify the candidate genes and genomic regions associated with meat quality traits for beef cattle, including fat color, meat color, marbling score, longissimus muscle area, and shear force. In our study, we identified twenty significant single-nucleotide polymorphisms (SNPs) (p < 1.47 × 10^?6) associated with these five meat quality traits. Notably, we observed several SNPs were in or near eleven genes which have been reported previously, including TMEM236, SORL1, TRDN, S100A10, AP2S1, KCTD16, LOC506594, DHX15, LAMA4, PREX1, and BRINP3. We identified a haplotype block on BTA13 containing five significant SNPs associated with fat color trait. We also found one of 19 SNPs was associated with multiple traits (shear force and longissimus muscle area) on BTA7. Our results offer valuable insights to further explore the potential mechanism of meat quality traits in Simmental beef cattle.     

A Genetic Analysis of the Werner Syndrome Region on Human Chromosome 8p

Werner syndrome (WRN) is an inherited disorder that produces symptoms of premature aging. This disease is caused by a recessive mutation that has previously been mapped to chromosome 8p. We have now used genetic linkage analysis to map the WRN gene relative to chromosome 6 reference loci, to screen candidate genes, and to identify a novel dinucleotide repeat polymorphic marker closely linked to WRN. The WRN locus was mapped relative to the marker loci, PLAT, ANK1, D8S135, and D8S87 of the comprehensive chromosome 8 linkage map. The heregulin (HRG) and the fibroblast growth factor receptor 1 genes (FGFR1) have been mapped to chromosome 8p and are involved in cellular growth. Recombination events were detected between WRN and the HRG and FGFR1 genes, excluding them as candidates for the WRN gene. A polymorphic marker generated in this study, WT251, is linked to WRN at a recombination fraction of 0.006, with a lod score of 16.5.     

Cognitive function in childhood and lifetime cognitive change in relation to mental wellbeing in four cohorts of older people

Background

Poorer cognitive ability in youth is a risk factor for later mental health problems but it is largely unknown whether cognitive ability, in youth or in later life, is predictive of mental wellbeing. The purpose of this study was to investigate whether cognitive ability at age 11 years, cognitive ability in later life, or lifetime cognitive change are associated with mental wellbeing in older people.

Methods

We used data on 8191 men and women aged 50 to 87 years from four cohorts in the HALCyon collaborative research programme into healthy ageing: the Aberdeen Birth Cohort 1936, the Lothian Birth Cohort 1921, the National Child Development Survey, and the MRC National Survey for Health and Development. We used linear regression to examine associations between cognitive ability at age 11, cognitive ability in later life, and lifetime change in cognitive ability and mean score on the Warwick Edinburgh Mental Wellbeing Scale and meta-analysis to obtain an overall estimate of the effect of each.

Results

People whose cognitive ability at age 11 was a standard deviation above the mean scored 0.53 points higher on the mental wellbeing scale (95% confidence interval 0.36, 0.71). The equivalent value for cognitive ability in later life was 0.89 points (0.72, 1.07). A standard deviation improvement in cognitive ability in later life relative to childhood ability was associated with 0.66 points (0.39, 0.93) advantage in wellbeing score. These effect sizes equate to around 0.1 of a standard deviation in mental wellbeing score. Adjustment for potential confounding and mediating variables, primarily the personality trait neuroticism, substantially attenuated these associations.

Conclusion

Associations between cognitive ability in childhood or lifetime cognitive change and mental wellbeing in older people are slight and may be confounded by personality trait differences.