Antony Payton | The University of Manchester (original) (raw)

Papers by Antony Payton

Molecular Psychiatry, 2014

Cognitive decline is a feared aspect of growing old. It is a major contributor to lower quality o... more 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 549 692 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 ¼ 2.5 Â 10 À 8 ). This result was replicated in a meta-analysis of three independent Swedish cohorts (P ¼ 2.41 Â 10 À 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 ¼ 2.18 Â 10 À 8 ; females, P ¼ 1.66 Â 10 À 11 ; males, P ¼ 0.01). Fine SNP mapping of the TOMM40/APOE region identified both APOE (rs429358; P ¼ 3.66 Â 10 À 11 ) and TOMM40 (rs11556505; P ¼ 2.45 Â 10 À 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.

Journal of Alzheimer's disease : JAD, 2014

Alzheimer's disease (AD) and non-pathological cognitive aging have phenotypic similarities wh... more Alzheimer's disease (AD) and non-pathological cognitive aging have phenotypic similarities which may be influenced by an overlapping set of genetic variants. Genome-wide complex trait analysis estimates that common genetic variants account for about 24% of the variation contributing to liability for AD. It is also estimated that 24% of the variance of non-pathological cognitive aging is accounted for by common single nucleotide polymorphisms. However, although the APOE locus is associated with both AD and cognitive aging, it is not known to what extent other common genetic variants, with smaller effect sizes that influence both, overlap. We test the hypothesis that polygenic risk for AD is associated with cognitive ability and cognitive change in about 3,000 non-demented older people (Cognitive Ageing Genetics England and Scotland-CAGES-consortium). We found no significant association of polygenic risk for AD with cognitive ability or cognitive change in CAGES, indicating that t...

American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics, Jan 7, 2015

Cognitive deficits and reduced educational achievement are common in psychiatric illness; underst... more Cognitive deficits and reduced educational achievement are common in psychiatric illness; understanding the genetic basis of cognitive and educational deficits may be informative about the etiology of psychiatric disorders. A recent, large genome-wide association study (GWAS) reported a genome-wide significant locus for years of education, which subsequently demonstrated association to general cognitive ability ("g") in overlapping cohorts. The current study was designed to test whether GWAS hits for educational attainment are involved in general cognitive ability in an independent, large-scale collection of cohorts. Using cohorts in the Cognitive Genomics Consortium (COGENT; up to 20,495 healthy individuals), we examined the relationship between g and variants associated with educational attainment. We next conducted meta-analyses with 24,189 individuals with neurocognitive data from the educational attainment studies, and then with 53,188 largely independent individuals ...

Psychiatric genetics, 2003

There has been a recent resurgence in interest in the role of autoimmunity in childhood neuropsyc... more There has been a recent resurgence in interest in the role of autoimmunity in childhood neuropsychiatric disorders. Significant association between HLA-DRB1 and attention deficit hyperactivity disorder (ADHD) in a case-control study of 31 subjects has been reported but there have been no other published studies following up these results. We attempted to replicate these findings. In a well-characterized sample of 173 children with ADHD, using a fully automated sequence-specific oligonucleotide method for HLA genotyping, association between ADHD and HLA-DRB1 was tested for using the Transmission Disequilibrium Test and case-control analysis. Transmission Disequilibrium Test analysis yielded a chi-square of 10.694 with a simulated global P value of 0.1641 for the full sample, and a chi-square value of 11.307 with a simulated global P value of 0.1323 for the complete trios only. There was no evidence of association of HLA-DRB1 and ADHD.

European Journal of Human Genetics, 2008

A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability i... more A 5-single nucleotide polymorphism (SNP) set has been associated with general cognitive ability in 5000 7-year-old children from the Twins Early Development Study (TEDS). Four of these SNPs were identified through a 10 K microarray analysis and one was identified through a targeted analysis of brain-expressed genes. The present study tested this association with general cognitive ability in six population samples of varying size and age from Australia, the UK (Scotland and England) and the Netherlands. Results from the largest sample (N=1310) approached significance (P=0.06) in the direction of the original finding, but results from the other samples (N=205-758) were mixed. A meta-analysis of the results--allowing for effect size heterogeneity between samples--yielded a non-significant correlation (r=-0.01, P=0.57), indicating that this SNP set was not associated with general cognitive ability in the populations studied.

European Journal of Pain Supplements, 2011

Cognitive abilities vary among people. About 40-50% of this variability is due to general intelli... more Cognitive abilities vary among people. About 40-50% of this variability is due to general intelligence (g), which reflects the positive correlation among individuals' scores on diverse cognitive ability tests. g is positively correlated with many life outcomes, such as education, occupational status and health, motivating the investigation of its underlying biology. In psychometric research, a distinction is made between general fluid intelligence (gF) -the ability to reason in novel situations -and general crystallized intelligence (gC) -the ability to apply acquired knowledge. This distinction is supported by developmental and cognitive neuroscience studies. Classical epidemiological studies and recent genome-wide association studies (GWASs) have established that these cognitive traits have a large genetic component. However, no robust genetic associations have been published thus far due largely to the known polygenic nature of these traits and insufficient sample sizes. Here, using two GWAS datasets, in which the polygenicity of gF and gC traits was previously confirmed, a gene-and pathway-based approach was undertaken with the aim of characterizing and differentiating their genetic architecture. Pathway analysis, using genes selected on the basis of relaxed criteria, revealed notable differences between these two traits. gF appeared to be characterized by genes affecting the quantity and quality of neurons and therefore neuronal efficiency, whereas long-term depression (LTD) seemed to underlie gC. Thus, this study supports the gF-gC distinction at the genetic level and identifies functional annotations and pathways worthy of further investigation.

Translational Psychiatry, 2014

Differences in general cognitive ability (intelligence) account for approximately half of the var... more 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.

Journal of Neurology Neurosurgery and Psychiatry, 2006

Objective: To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are as... more Objective: To determine whether polymorphic variations in the apolipoprotein E gene (APOE) are associated with increased risk of frontotemporal lobar degeneration (FTLD) when mutation in tau gene is absent.Methods: The APOE gene was genotyped by polymerase chain reaction from DNA routinely extracted from blood or brain tissues. The APOE ε4 allele frequency in 198 patients with FTLD not associated with

Molecular Psychiatry - MOL PSYCHIATR, 2000

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition of ea... more 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 c...

The Journal of Steroid Biochemistry and Molecular Biology, 2005

Venous ulcers are the predominant form of chronic wound in the elderly, accounting for around 70%... more Venous ulcers are the predominant form of chronic wound in the elderly, accounting for around 70% of all cases. The steroid sex hormone estrogen plays a crucial role in normal human skin maintenance and during cutaneous wound repair following injury. Estrogen can reverse agerelated impaired wound healing by dampening the inflammatory response and increasing matrix deposition at the wound site. The molecular actions of estrogen are mediated through two nuclear sex steroid hormone receptors, estrogen receptor alpha (ER␣) and beta (ER␤). We have conducted a case-control study to investigate whether dinucleotide repeat polymorphisms in the estrogen receptor genes are associated with venous ulceration in the UK Caucasian population. Genomic fragments containing the ER␣ dinucleotide (TA) n repeat polymorphism or the ER␤ dinucleotide (CA) n repeat polymorphism were amplified by polymerase chain reaction in subject DNA samples and genotyped according to fragment length by capillary electrophoresis. There was no evidence to suggest that the TA repeat polymorphism of ER␣ was associated with venous ulceration. However, the CA*18 allele of the ER␤ CA repeat polymorphism was significantly associated with venous ulceration (n = 120, OR = 1.8, 95% CI = 1.1-2.8, P = 0.02). When the CA repeats alleles were grouped together into either low (L ≤ 18) or high (H > 18) numbers of CA repeats, the low (L) repeat allele was significantly associated with venous ulceration (OR = 1.5, 95% CI = 1.0-2.2, P = 0.03). Our results show that a specific ER␤ variant is associated with impaired healing in the elderly, predisposing individuals to venous ulceration.

Psychiatry Research, 2001

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, and molecular gen... more Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder, and molecular genetic studies are underway, with most researchers focusing on identifying susceptibility genes in clinical samples with ADHD. An alternative approach is to search for quantitative trait loci underlying the trait measure of ADHD in non-clinical samples. Positive findings of association of the dopamine transporter DAT1 480 bp allele (allele 10) and the DRD4 7 repeat allele with clinical ADHD have been previously reported. In this pilot study, we examined these polymorphisms in a selected population-based sample of twins (50 high scoring pairs, 42 low scoring pairs). There was a trend for an increase in the frequency of the dopamine receptor DRD4 7 repeat allele in the high-scoring concordant monozygotic twins (odds ratio=1.4). Although this result was not statistically significant, the frequency of the 7 repeat allele was similar to that reported for our clinic sample of ADHD patients drawn from the same geographical area. There was a non-significant trend for an increased frequency of the DAT1 allele 10 (odds ratio=1.3). These results suggest that a molecular genetic study based on a questionnaire-derived measure of ADHD in a non-clinical sample is feasible and the results appear to be comparable with those from studies of clinical cases. However, sample size and power are key issues to consider when using this approach.

Neuroscience Letters, 2009

Neuropsychopharmacology, 2010

Decision-making, choosing the best option from the possible outcomes, is impaired in many psychia... more Decision-making, choosing the best option from the possible outcomes, is impaired in many psychiatric conditions including affective disorders. We tested the hypothesis that variations in serotonergic genes (TPH2, TPH1, SLC6A4, HTR1A), which influence serotonin availability, affect choice behavior in a probabilistic gambling task. A population cohort (N=1035) completed a paper-and-pencil gambling task, filled out personality and symptom questionnaires and gave consent for the use of their DNA in a genetic association study. A subgroup of subjects (N=69) also completed a computer version of the task. The gambling task was designed to estimate an individual's tendency to take a risk when choosing between a smaller but more certain 'win' and a larger, less probable one. We genotyped 7 haplotype tagging SNPs in the TPH2 gene, and previously reported functional polymorphisms from the other genes (rs1800532, 5HTTLPR and rs6295). Carriers of the more prevalent TPH2 haplotype, which was previously associated with less active enzyme variant, showed reduced risk-taking on both tasks compared with subjects not carrying the common haplotype. The effect of TPH2 haplotypes on risk-taking was independent of current depression and anxiety symptoms, neuroticism and impulsiveness scores. We did not find an association between functional polymorphisms in the TPH1, SLC6A4, HTR1A genes and risk-taking behavior. In conclusion, our study demonstrates the role of the TPH2 gene, and the serotonin system, in risk-taking and suggests that TPH2 gene may contribute to the expression of psychiatric phenotypes through altered decision-making.

Neuropsychopharmacology, 2009

Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helples... more Cannabinoid receptor 1 (CB1) gene (CNR1) knockout mice are prone to develop anhedonic and helpless behavior after chronic mild stress. In humans, the CB1 antagonist rimonabant increases the risk of depressed mood disorders and anxiety. These studies suggest the hypothesis that genetic variation in CB1 receptor function influences the risk of depression in humans in response to stressful life events. In a population sample (n ¼ 1269), we obtained questionnaire measures of personality (Big Five Inventory), depression and anxiety (Brief Symptom Inventory), and life events. The CNR1 gene was covered by 10 SNPs located throughout the gene to determine haplotypic association. Variations in the CNR1 gene were significantly associated with a high neuroticism and low agreeableness phenotype (explained variance 1.5 and 2.5%, respectively). Epistasis analysis of the SNPs showed that the previously reported functional 5 0 end of the CNR1 gene significantly interacts with the 3 0 end in these phenotypes. Furthermore, current depression scores significantly associated with CNR1 haplotypes but this effect diminished after covariation for recent life events, suggesting a gene Â environment interaction. Indeed, rs7766029 showed highly significant interaction between recent negative life events and depression scores. The results represent the first evidence in humans that the CNR1 gene is a risk factor for depression--and probably also for co-morbid psychiatric conditions such as substance use disorders--through a high neuroticism and low agreeableness phenotype. This study also suggests that the CNR1 gene influences vulnerability to recent psychosocial adversity to produce current symptoms of depression.

Neurobiology of Aging, 2010

NAD(P)H dehydrogenase quinone 2 (NQO2) is a quinone reductase whose functions include the reducti... more NAD(P)H dehydrogenase quinone 2 (NQO2) is a quinone reductase whose functions include the reduction of both oxidative stress during the redox cycle and neurotoxicity caused by the metabolism of catecholamines. We have investigated a functional non-synonymous exon 3 single nucleotide polymorphism (rs1143684) within the NQO2 gene for association with cognitive decline using a cohort of 722 communitydwelling older individuals aged 50 years and over. The volunteers had completed tests that measured fluid intelligence, processing speed, immediate/delayed verbal recall and semantic memory. We observed a nominal significant association between this polymorphism and the trajectory of delayed memory recall over time (p = 0.029). No other associations were seen with the decline of other cognitive abilities.

Molecular Psychiatry, 2011

General intelligence is an important human quantitative trait that accounts for much of the varia... more 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 1,2 . Data from twin and family studies are consistent with a high heritability of intelligence 3 , but this inference has been controversial. We conducted a genome-wide analysis of 3511 unrelated adults with data on 549 692 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 approximately 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.

Molecular Psychiatry, 2000

... 1 2) ; GU NF (3) ; FENG GY (3) ; ZOU FG (1) ; XING YL (4) ; SHI JG (4) ; ZHAO SM (4) ; ZHU SM... more ... 1 2) ; GU NF (3) ; FENG GY (3) ; ZOU FG (1) ; XING YL (4) ; SHI JG (4) ; ZHAO SM (4) ; ZHU SM (5) ; JI LP (5) ; SUN WW (6) ; ZHENG YL (1) ; LIU WQ (1) ; BREEN G. (7) ; ST CLAIR D. (7 ... INIST-CNRS, Cote INIST : 26439, 35400010322478.0140. Nº notice refdoc (ud4) : 13409384. ...

Molecular Psychiatry, 2003

General intelligence is a heritable trait that is a risk factor for both the onset of dementia an... more 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 ¼ 0.01) between a functional C4T (Ala4Val) 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.

Journal of Psychiatric Research, 2009

Background: Several lines of evidence implicate BDNF in the pathophysiology of psychiatric illnes... more Background: 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 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. Methods: 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. Results: 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. Conclusions: 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.