Publications by authors named "Antony Payton"

72 Publications

Systematic review of associations between HLA and renal function.

Int J Immunogenet 2022 Feb 17;49(1):46-62. Epub 2021 Dec 17.

Faculty of Biology, Medicine and Health, Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, University of Manchester, Manchester, England.

Introduction: Kidney dysfunction is a highly significant disease, both in the United Kingdom and globally. Many previous studies have reported associations between human leukocyte antigens (HLA) and renal function; this systematic review attempts to identify, summarize and appraise all published studies of these associations.

Methods: A literature search was performed using Medline, Embase and Cochrane Central Register of Controlled Trials to identify papers whose keywords included each of the following concepts: HLA, renal failure and genetic association. A total of 245 papers were identified and assessed for eligibility; 35 of these were included in the final study.

Results: A total of 95 HLA types and 14 three-locus haplotypes were reported to be associated with either increased or decreased renal function. A number of these findings were replicated by independent studies that reported 16 types were protective against renal dysfunction and 15 types were associated with reduced renal function. A total of 20 HLA types were associated with both increased risk of renal disease and decreased risk by independent studies.

Discussion: There is very little consensus on which HLA types have a protective or deleterious effect on renal function. Ethnicity may play a role, with HLA types possibly having different effects among different populations, and it is possible that the different primary diseases that lead to ESRD may have different HLA associations. Some of the studies may contain type I and type II errors caused by insufficient sample sizes, cohort selection and statistical methods. Although we have compiled a comprehensive list of published associations between renal function and HLA, in many cases, it is unclear which associations are reliable. Further studies are required to confirm or refute these findings.
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http://dx.doi.org/10.1111/iji.12566DOI Listing
February 2022

Telephone Interview for Cognitive Status Scores Associate with Cognitive Impairment and Alzheimer's Disease Pathology at Death.

J Alzheimers Dis 2021 ;84(2):609-619

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

Background: Early diagnosis of Alzheimer's disease (AD) provides an opportunity for early intervention. Cognitive testing has proven to be a reliable way to identify individuals who may be at risk of AD. The Telephone Assessment for Cognitive Screening (TICS) is proficient in screening for cognitive impairment. However, its ability to identify those at risk of developing AD pathology is unknown.

Objective: We aim to investigate associations between TICS scores, collected over a period of 13 years, and the cognitive status of participants at death. We also examine relationships between TICS scores and neuropathological indices of AD (CERAD score, Thal phase, and Braak stage).

Methods: Between 2004 and 2017, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent cognitive assessment using TICS. Scores from four time points were available for analysis. Cognitive impairment and AD pathology at death was evaluated in 101 participants.

Results: TICS scores at time points 2, 3, and 4 were significantly lower in those cognitively impaired at death compared to those considered cognitively normal. There were significant negative correlations between TICS scores and CERAD score and Braak stage at time points 2 and 4. No correlations between Thal phase and TICS were found.

Conclusion: Findings indicate that TICS could be used not only to screen for cognitive impairment, but also to identify individuals at risk of developing AD pathology, many years before any overt symptoms occur. Once identified, 'at risk' individuals could be targeted for early interventions which could attenuate the progression of the disease.
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http://dx.doi.org/10.3233/JAD-215102DOI Listing
January 2022

The effect of season of birth on brain epigenome-wide DNA methylation of older adults.

J Dev Orig Health Dis 2021 Jul 26:1-11. Epub 2021 Jul 26.

Division of Neuroscience & Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Perinatal light exposure predisposes towards health and behaviour in adulthood. Season of birth is associated with psychiatric, allergic, cardiovascular and metabolic problems. It has been proposed that early-life environmental light disrupts the development of biological rhythms which, in turn, influence later-life health. However, the mechanisms linking perinatal seasonal light to later-life biological rhythm and health in humans are unknown. In this study, we investigated the association between season of birth and epigenome-wide DNA methylation of two postmortem human brain regions (16 hypothalamus, 14 temporal cortex). We did not find statistically significant differences at the whole epigenome level, either because we lacked statistical power or that no association exists. However, when we examined 24 CpG sites that had the highest significance or differential methylation, we identified regions which may be associated with circadian rhythm entrainment, cholinergic neurotransmission and neural development. Amongst methylation of the core clock genes, we identified that hypothalamus Neuronal PAS Domain Protein 2 (NPAS2) gene has hypermethylated regions in long photoperiod-born individuals. In addition, we found nominal associations between season of birth and genes linked to chronotype and narcolepsy. Season of birth-related brain DNA methylation profile was different than a previously reported blood methylation profile, suggesting a tissue-specific mechanism of perinatal light programming. Overall, we are the first to analyse the relationship between season of birth and human brain DNA methylation. Further studies with larger sample sizes are required to confirm an imprinting effect of perinatal light on the circadian clock.
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http://dx.doi.org/10.1017/S2040174421000453DOI Listing
July 2021

Superior Frontal Gyrus Locus DNA Methylation in Alzheimer's Disease.

J Alzheimers Dis Rep 2021 Apr 6;5(1):275-282. Epub 2021 Apr 6.

Department of Life Sciences, Manchester Metropolitan University, Manchester, UK.

Background: The ɛ4 allele is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). The neighboring gene has also been implicated in AD due to its close proximity to .

Objective: Here we tested whether methylation of the locus may influence ApoE protein levels and AD pathology.

Methods: DNA methylation levels across the locus and ApoE levels were measured in superior frontal gyrus tissues of 62 human brains genotyped for and scored for AD neuropathology.

Results: Methylation levels within the CpG island in the promoter or CpG island in Exon 4 did not differ between ɛ4 carriers versus non-carriers. However, ɛ4 carriers had significantly higher methylation the promoter compared with non-carriers. Although DNA methylation at , promoter region, or did not differ between AD pathological groups, there was a negative association between methylation and CERAD scores. ApoE protein concentrations did not significantly different between ɛ4 carriers and non-carriers, or between AD pathological groups. Finally, there was no correlation between ApoE protein concentrations and DNA methylation levels.

Conclusion: gene methylation may not be affected by genotype, relate to AD pathology or ApoE protein levels in the superior frontal gyrus, though, DNA methylation at the ApoE promoter differed between genotype. DNA methylation at associated with amyloid-β plaques and longitudinal fluid intelligence. In sum, these results suggest a complicated regulation of the locus in the brain in controlling ApoE protein levels and AD neuropathology.
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http://dx.doi.org/10.3233/ADR-201000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150259PMC
April 2021

Identifying nootropic drug targets via large-scale cognitive GWAS and transcriptomics.

Neuropsychopharmacology 2021 09 25;46(10):1788-1801. Epub 2021 May 25.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Broad-based cognitive deficits are an enduring and disabling symptom for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. While novel drug targets for schizophrenia and depression have emerged from recent large-scale genome-wide association studies (GWAS) of these psychiatric disorders, GWAS of general cognitive ability can suggest potential targets for nootropic drug repurposing. Here, we (1) meta-analyze results from two recent cognitive GWAS to further enhance power for locus discovery; (2) employ several complementary transcriptomic methods to identify genes in these loci that are credibly associated with cognition; and (3) further annotate the resulting genes using multiple chemoinformatic databases to identify "druggable" targets. Using our meta-analytic data set (N = 373,617), we identified 241 independent cognition-associated loci (29 novel), and 76 genes were identified by 2 or more methods of gene identification. Actin and chromatin binding gene sets were identified as novel pathways that could be targeted via drug repurposing. Leveraging our transcriptomic and chemoinformatic databases, we identified 16 putative genes targeted by existing drugs potentially available for cognitive repurposing.
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http://dx.doi.org/10.1038/s41386-021-01023-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8357785PMC
September 2021

Early changes in visuospatial episodic memory can help distinguish primary age-related tauopathy from Alzheimer's disease.

Neuropathol Appl Neurobiol 2021 12 29;47(7):1114-1116. Epub 2021 May 29.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

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http://dx.doi.org/10.1111/nan.12726DOI Listing
December 2021

Analysis of human total antibody repertoires in TIF1γ autoantibody positive dermatomyositis.

Commun Biol 2021 03 26;4(1):419. Epub 2021 Mar 26.

Division of Population Health, Health Services Research & Primary Care, University of Manchester, Manchester, UK.

We investigate the accumulated microbial and autoantigen antibody repertoire in adult-onset dermatomyositis patients sero-positive for TIF1γ (TRIM33) autoantibodies. We use an untargeted high-throughput approach which combines immunoglobulin disease-specific epitope-enrichment and identification of microbial and human antigens. We observe antibodies recognizing a wider repertoire of microbial antigens in dermatomyositis. Antibodies recognizing viruses and Poxviridae family species are significantly enriched. The identified autoantibodies recognise a large portion of the human proteome, including interferon regulated proteins; these proteins cluster in specific biological processes. In addition to TRIM33, we identify autoantibodies against eleven further TRIM proteins, including TRIM21. Some of these TRIM proteins share epitope homology with specific viral species including poxviruses. Our data suggest antibody accumulation in dermatomyositis against an expanded diversity of microbial and human proteins and evidence of non-random targeting of specific signalling pathways. Our findings indicate that molecular mimicry and epitope spreading events may play a role in dermatomyositis pathogenesis.
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http://dx.doi.org/10.1038/s42003-021-01932-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997983PMC
March 2021

Early life factors and COVID-19 infection in England: A prospective analysis of UK Biobank participants.

Early Hum Dev 2021 04 4;155:105326. Epub 2021 Feb 4.

Division of Informatics, Imaging & Data Sciences, The University of Manchester, UK.

This study aims to examine whether maternal smoking, birth weight, birth month and breastfeeding are associated with COVID-19 infection and hospitalisation. Maternal smoking was positively associated with COVID-19 infection. Breastfeeding was negatively associated with COVID-19 infection. The odds of being hospitalised due to COVID-19 were higher among those who had lower birthweight and mothers who were smoking during pregnancy.
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http://dx.doi.org/10.1016/j.earlhumdev.2021.105326DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7860946PMC
April 2021

Associations between human leukocyte antigens and renal function.

Sci Rep 2021 02 4;11(1):3158. Epub 2021 Feb 4.

Transplantation Laboratory, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK.

Human leukocyte antigens (HLA) have been associated with renal function, but previous studies report contradictory findings with little consensus on the exact nature or impact of this observation. This study included 401,307 white British subjects aged 39-73 when they were recruited by UK Biobank. Subjects' HLA types were imputed using HLA*IMP:02 software. Regression analysis was used to compare 362 imputed HLA types with estimated glomerular filtration rate (eGFR) as a primary outcome and clinical indications as secondary outcome measures. 22 imputed HLA types were associated with increased eGFR (and therefore increased renal function). Decreased eGFR (decreased renal function) was associated with 11 imputed HLA types, seven of which were also associated with increased risk of end-stage renal disease and/or chronic kidney disease. Many of these HLA types are commonly inherited together in established haplotypes, for example: HLA-A*01:01, B*08:01, C*07:01, DRB1*03:01, DQB1*02:01. This haplotype has a population frequency of 9.5% in England and each allele was associated with decreased renal function. 33 imputed HLA types were associated with kidney function in white British subjects. Linkage disequilibrium in HLA heritance suggests that this is not random and particularly affects carriers of established haplotypes. This could have important applications for the diagnosis and treatment of renal disease and global population health.
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http://dx.doi.org/10.1038/s41598-021-82361-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862310PMC
February 2021

Influence of APOE genotype in primary age-related tauopathy.

Acta Neuropathol Commun 2020 12 7;8(1):215. Epub 2020 Dec 7.

Division of Neuroscience and Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, Salford Royal Hospital, The University of Manchester, Salford, M6 8HD, UK.

The term "Primary age-related tauopathy" (PART) was coined in 2014 to describe the common neuropathological observation of neurofibrillary tangles without associated beta-amyloid (Aβ) pathology. It is possible for PART pathology to be present in both cognitively normal and cognitively impaired individuals. Genetically, Apolipoprotein E (APOE) ε4 has been shown to occur less commonly in PART than in Alzheimer's disease (AD). Here, we investigate the relationships between PART, AD and those pathologically normal for age, with an emphasis on APOE and cognition, using 152 selected participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and the Manchester arm of the Brains for Dementia Research cohort. APOE genotype differed between PART and AD with APOE ε2 more common in the former and APOE ε4 more common in the latter. Individuals with definite PART were less likely to be cognitively impaired than those with AD and those with pathology considered pathologically normal for age. We postulate that the lack of Aβ in definite PART cases may be due either to an increased frequency of APOE ε2 or decreased frequency of APOE ε4 as their resulting protein isoforms have differing binding properties in relation to Aβ. Similarly, an increased frequency of APOE ε2 or decreased frequency of APOE ε4 may lead to decreased levels of cognitive impairment, which raises questions regarding the impact of Aβ pathology on overall cognition in elderly subjects. We suggest that it may be possible to use the increased frequency of APOE ε2 in definite PART to assist neuropathological diagnosis.
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http://dx.doi.org/10.1186/s40478-020-01095-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7720601PMC
December 2020

Mid to late-life scores of depression in the cognitively healthy are associated with cognitive status and Alzheimer's disease pathology at death.

Int J Geriatr Psychiatry 2021 05 20;36(5):713-721. Epub 2020 Nov 20.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

Objectives: Early diagnosis of Alzheimer's disease (AD) is essential for early interventions. Symptoms of depression could represent a prodromal stage of AD. Very early mood alterations may help to stratify those at highest risk of late-life AD. We aim to investigate associations between baseline/longitudinal scores for depression, presence of cognitive impairment and/or AD pathology at death.

Methods/design: Between 1991 and 2015, participants from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age underwent 10 waves of assessment using the Geriatric Depression Scale (GDS). AD pathology at death was evaluated in 106 eligible cases. Analyses aimed to examine associations between GDS scores, cognitive status and AD pathology (as measured by Braak stage, Thal phase and CERAD).

Results: Baseline GDS scores were significantly higher for those cognitively impaired at death than those cognitively normal. Significantly higher baseline GDS scores were found for those with greater Consortium to Establish a Registry for Alzheimer's Disease (CERAD) scores than those with lower CERAD scores. Similarly, significantly higher baseline GDS scores were found for those with a greater Braak stage than those with lower tau burden. These correlations remained after controlling for age at death, education and APOE ε4, but were less robust. Mean longitudinal GDS scores associated with cognition but not pathology.

Conclusions: GDS scores collected approximately 20 years before death were associated with cognitive status and AD pathology at death. We postulate that early AD-related pathological change produces raised GDS scores due to an overlapping neural basis with depression, and that this may be considered as an early diagnostic marker for AD.
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http://dx.doi.org/10.1002/gps.5470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048934PMC
May 2021

Human leukocyte antigen associations with renal function among ethnic minorities in the United Kingdom.

HLA 2020 12 5;96(6):697-708. Epub 2020 Nov 5.

Transplantation Laboratory, Manchester Royal Infirmary, Manchester University NHS Foundation Trust, Manchester, UK.

Human leukocyte antigens (HLA) have been associated with renal function, but previous studies report contradictory findings. There has been a lack of research into how HLA affects renal function in Black, Asian and Minority Ethnic (BAME) people in the UK, despite BAME people being disproportionately affected by renal dysfunction. This study included >27 000 UK Biobank subjects of six ethnicities (>12 100 Irish, >5400 Indian, >4000 Black Caribbean, >3000 Black African, >1600 Pakistani, and >1400 Chinese) aged 39 to 73. Subjects' high-resolution HLA genotypes were imputed using HLA*IMP:02 software. Regression analysis was used to compare 108 imputed HLA alleles with two measures of estimated glomerular filtration rate (eGFR): one based on serum creatinine; one based on serum cystatin. Secondary analysis compared CKD stage 2 subjects to healthy controls. Nine imputed HLA alleles were associated with eGFR (adjusted P < .05). Six associations were based on creatinine in Black African subjects: HLA-B*53:01 (beta = -2.628, adjusted P = 4.69 × 10 ); C*04:01 (beta = -1.667, adjusted P = .0269); DPA1*02:01 (beta = -1.569, adjusted P = .0182); and DPA1*02:02 (beta = -1.716, adjusted P = .0251) were linked to decreased renal function, while DRB1*03:01 (beta = 3.200, adjusted P = 3.99 × 10 ) and DPA1*01:03 (beta = 2.276, adjusted P = 2.31 × 10 ) were linked to increased renal function. Two of these (HLA-B*53:01 and C*04:01) are commonly inherited together. In Irish subjects, HLA-DRB1*04:01 (beta = 1.075, adjusted P = .0138) was linked to increased eGFR (based on cystatin); in Indian subjects, HLA-DRB1*03:01 (beta = -1.72, adjusted P = 4.78 × 10 ) and DQB1*02:01 (beta = -1.755, adjusted P = 2.26 × 10 )were associated with decreased eGFR (based on cystatin). No associations were found in the other three ethnic groups. Nine HLA alleles appear to be associated with kidney function in BAME people in the UK. This could have applications for the diagnosis and treatment of renal disease and could help reduce health inequalities in the UK.
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http://dx.doi.org/10.1111/tan.14078DOI Listing
December 2020

Novel Mutations and Genes That Impact on Growth in Short Stature of Undefined Aetiology: The EPIGROW Study.

J Endocr Soc 2020 Oct 10;4(10):bvaa105. Epub 2020 Sep 10.

Developmental Biology & Medicine, Faculty of Biology, Medicine & Health, University of Manchester and Manchester Academic Health Science Centre, Manchester, United Kingdom.

Background: Children with short stature of undefined aetiology (SS-UA) may have undiagnosed genetic conditions.

Purpose: To identify mutations causing short stature (SS) and genes related to SS, using candidate gene sequence data from the European EPIGROW study.

Methods: First, we selected exonic single nucleotide polymorphisms (SNPs), in cases and not controls, with minor allele frequency (MAF) < 2%, whose carriage fitted the mode of inheritance. Known mutations were identified using Ensembl and gene-specific databases. Variants were classified as pathogenic, likely pathogenic, or variant of uncertain significance using criteria from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. If predicted by ≥ 5/10 algorithms (eg, Polyphen2) to be deleterious, this was considered supporting evidence of pathogenicity. Second, gene-based burden testing determined the difference in SNP frequencies between cases and controls across all and then rare SNPs. For genotype/phenotype relationships, we used PLINK, based on haplotype, MAF > 2%, genotype present in > 75%, and Hardy Weinberg equilibrium  > 10.

Results: First, a diagnostic yield of 10% (27/263) was generated by 2 pathogenic (nonsense in ) and a further 25 likely pathogenic mutations, including previously known missense mutations in , , , , , and . Second, genes related to SS: all methods identified . Another 7 genes () were identified by both gene-based approaches and 6 () were identified by gene-based testing for all SNPs and PLINK.

Conclusions: Such panels improve diagnosis in SS-UA, extending known disease phenotypes. Fourteen genes related to SS included some known to cause growth disorders as well as novel targets.
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http://dx.doi.org/10.1210/jendso/bvaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482646PMC
October 2020

Epigenetic Regulation of BMAL1 with Sleep Disturbances and Alzheimer's Disease.

J Alzheimers Dis 2020 ;77(4):1783-1792

Department of Life Sciences, Manchester Metropolitan University, Manchester, United Kingdom.

Background: An early symptom of Alzheimer's disease (AD) is a disturbance of the circadian rhythm that is associated with disrupted sleep/wake cycles.

Objective: To investigate if BMAL1, a key gene that drives the circadian cycle, is epigenetically regulated in brains in relation to longitudinal changes in cognition, sleep quality, and AD neuropathology.

Methods: Frontal cortex tissues were acquired from the Manchester Brain Bank (N = 96). DNA methylation at six CpG sites at the promoter of BMAL1, determined using bisulfite pyrosequencing, was tested for associations with Braak stage, CERAD score and Thal phase, longitudinal changes in cognition, sleep measurements and cross-section measures of depressive symptoms (BDI score).

Results: Methylation across all the CpGs strongly correlated with each other. We found increased CpG2 methylation with higher Braak (t(92), p = 0.015) and CERAD (t(94), p = 0.044) stages. No significance was found between longitudinal fluid intelligence, processing speed and memory tests, but methylation at CpG1 (r = 0.20, p = 0.05) and CpG4 (r = 0.20, p = 0.05) positively correlated with vocabulary. CpG2 positively correlated with cross-sectional fluid intelligence (r = 0.20 p = 0.05) and vocabulary (r = 0.22 p = 0.03). Though longitudinal analysis revealed no significance between sleep duration, midsleep and efficiency for any of the CpG sites, CpG3 (B = 0.03, 95% CI, p = 0.03) and CpG5 (B = 0.04, 95% CI, p = 0.01) significantly correlated with night wake. CpG4 correlated with depressive symptoms (B = -0.27, 95% CI, p = 0.02).

Conclusion: Methylation of BMAL1 associated with tau pathology, changes in cognitive measures, a measure of sleep and depressive symptoms, suggesting an involvement of the circadian cycle.
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http://dx.doi.org/10.3233/JAD-200634DOI Listing
September 2021

Influence of Genotype on Mortality and Cognitive Impairment.

J Alzheimers Dis Rep 2020 Jul 23;4(1):281-286. Epub 2020 Jul 23.

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

While many studies have examined the associations between genotype and mortality, findings have often been conflicting and it remains unclear whether genotype affects longevity. Using selected individuals from the Manchester arm of the Brains for Dementia Research programme and University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, we investigated relationships between genotype and age at death in both cognitively normal and cognitively impaired individuals. Results indicated that carrying the 4 allele led to a reduced chance in an individual reaching 80+ years and remaining cognitively healthy. Conversely, 2 carriers tended to live longer and remain cognitively normal. These findings add to the evidence that genotype influences longevity, especially in cognitively impaired individuals who carry the 4 allele.
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http://dx.doi.org/10.3233/ADR-200203DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7458549PMC
July 2020

The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology.

J Alzheimers Dis 2020 ;77(3):1005-1015

Division of Neuroscience & Experimental Psychology, Faculty of Biology, Medicine and Health, School of Biological Sciences, The University of Manchester, Salford Royal Hospital, Salford, UK.

Background: The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment.

Objective: The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages.

Methods: We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment.

Results: We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia.

Conclusion: Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.
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http://dx.doi.org/10.3233/JAD-200339DOI Listing
September 2021

Regulation of interleukin 6 by a polymorphic CpG within the frontal cortex in Alzheimer's disease.

Neurobiol Aging 2020 08 15;92:75-81. Epub 2020 Apr 15.

Department of Life Sciences, Bioscience Research Centre, Manchester Metropolitan University, Manchester, UK. Electronic address:

The cytokine interleukin 6 (IL-6) has been linked to the pathogenesis of Alzheimer's disease (AD). This is the first study to investigate the genetic and epigenetic interactions in the control of IL-6 in human brain and its relation to AD neuropathology in prefrontal cortex tissues from AD and controls genotyped for the SNP -174 C/G rs1800795, a polymorphic CpG in which the G allele creates a CpG site. Within CC homozygotes there were significantly higher brain levels of IL-6 protein compared to G allele carriers. The C allele that resulted in an absence of methylation at a CpG was also associated with significant changes in methylation at neighboring CpGs. Furthermore, there were significant differences in methylation between CC and CG/GG at CpG sites in the AD and control groups. That DNA methylation was altered in the brains by the presence of rs1800795, which further correlated with protein levels suggests the presence of a polymorphic CpG and genetic-epigenetic interactions in the regulation of IL-6 in the prefrontal cortex within AD brains.
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http://dx.doi.org/10.1016/j.neurobiolaging.2020.04.008DOI Listing
August 2020

Interactions between season of birth, chronological age and genetic polymorphisms in determining later-life chronotype.

Mech Ageing Dev 2020 06 1;188:111253. Epub 2020 May 1.

Division of Informatics, Imaging & Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, UK.

Human chronotype, the temporal pattern of daily behaviors, is influenced by postnatal seasonal programming and ageing. The aim of this study was to investigate genetic variants that are associated with season of birth programming and longitudinal chronotype change. Longitudinal sleep timing and genotype data from 1449 participants were collected for up to 27 years. Gene-environment interaction analysis was performed for 445 candidate single nucleotide polymorphisms that have previously been associated with chronotype. Associations were tested using linear mixed model. We identified 67 suggestively significant genomic loci that have genotype-ageing interaction and 25 genomic loci that may have genotype-season of birth interaction in determining chronotype. We attempted to replicate the results using longitudinal data of the UK Biobank from approximately 30,000 participants. Biological functions of these genes suggest that epigenetic regulation of gene expression and neural development may have roles in these processes. The strongest associated gene for sleep trajectories was ALKBH5, which has functions of DNA repair and epigenetic regulation. A potential candidate gene for postnatal seasonal programming was SIRT1, which has previously been implicated in postnatal programming, ageing and longevity. Genetic diversity may explain the heterogeneity in ageing-related change of sleep timing and postnatal environmental programming of later-life chronotype.
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http://dx.doi.org/10.1016/j.mad.2020.111253DOI Listing
June 2020

Seasonality and season of birth effect in the UK Biobank cohort.

Am J Hum Biol 2020 11 28;32(6):e23417. Epub 2020 Mar 28.

Division of Informatics, Imaging & Data Sciences, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

Objectives: Humans live in environments that reduce the impact of seasonal cues. However, studies suggest that many aspects of human biology, such as birth, metabolism, health, and death are still annually rhythmic.

Methods: Using UK Biobank, a large (N = 502 536) population-based resource, we investigated the influence of seasonality on birth rate, basal metabolic rate, health, reaction speed, and sleep. We also investigated the association between season of birth and regional brain volumes, basal metabolic rate, health, reaction speed, and sleep.

Results: Our results showed that annual birth rate peaks in April and May. Individuals had the highest basal metabolic rate in December and January. Poorer subjective general health and slower reaction time were observed in May. Susceptibility to insomnia showed an opposite trend that peaked in autumn and winter. People reported shorter periods of sleep, easier waking, earlier chronotype, more daytime dozing, and napping in summer compared with winter. Our results suggest that season of birth may influence later-life characteristics. We also observed that the effect of season of birth is in the opposite direction of the seasonal rhythm for basal metabolic rate, reaction time, and insomnia. Moreover, our analysis showed that prevalence of allergy is higher among people born in spring compared to autumn.

Conclusions: Overall, our findings indicate a significant effect of seasonality on a range of human traits and that early-life seasons appear to have an effect on health and behaviors in adulthood.
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http://dx.doi.org/10.1002/ajhb.23417DOI Listing
November 2020

A Comparative Study of Pathological Outcomes in The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age and Brains for Dementia Research Cohorts.

J Alzheimers Dis 2020 ;73(2):619-632

Faculty of Biology, Medicine and Health, School of Biological Sciences, Division of Neuroscience & Experimental Psychology, The University of Manchester, Salford Royal Hospital, Salford, UK.

In the present study, we have characterized and compared individuals whose brains were donated as part of The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (UoM) with those donated through the Manchester arm of the UK Brains for Dementia Research (BDR) program. The aim of this study was to investigate how differences in study recruitment may affect final pathological composition of cohort studies. The UoM cohort was established as a longitudinal study of aging and cognition whereas the BDR program was established, prima facie, to collect brains from both demented and non-demented individuals for the purpose of building a tissue research resource. Consequently, the differences in recruitment patterns generated differences in demographic, clinical, and neuropathological characteristics. There was a higher proportion of recruits with dementia [mostly Alzheimer's disease (AD)] within the BDR cohort than in the UoM cohort. In pathological terms, the BDR cohort was more 'polarized', being more composed of demented cases with high Braak pathology scores and non-demented cases with low Braak scores, and fewer non-AD pathology cases, than the UoM cohort. In both cohorts, cerebral amyloid angiopathy tended to be greater in demented than non-demented individuals. Such observations partly reflect the recruitment of demented and non-demented individuals into the BDR cohort, and also that insufficient study time may have elapsed for disease onset and development in non-demented individuals to take place. Conversely, in the UoM cohort, where there had been nearly 30 years of study time, a broader spread of AD-type pathological changes had 'naturally' evolved in the brains of both demented and non-demented participants.
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http://dx.doi.org/10.3233/JAD-190580DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029329PMC
November 2020

GWAS Identifies 44 Independent Associated Genomic Loci for Self-Reported Adult Hearing Difficulty in UK Biobank.

Am J Hum Genet 2019 10 26;105(4):788-802. Epub 2019 Sep 26.

Department of Twin Research and Genetic Epidemiology, School of Life Course Sciences, King's College London, London SE1 7EH, UK. Electronic address:

Age-related hearing impairment (ARHI) is the most common sensory impairment in the aging population; a third of individuals are affected by disabling hearing loss by the age of 65. It causes social isolation and depression and has recently been identified as a risk factor for dementia. The genetic risk factors and underlying pathology of ARHI are largely unknown, meaning that targets for new therapies remain elusive, yet heritability estimates range between 35% and 55%. We performed genome-wide association studies (GWASs) for two self-reported hearing phenotypes, using more than 250,000 UK Biobank (UKBB) volunteers aged between 40 and 69 years. Forty-four independent genome-wide significant loci (p < 5E-08) were identified, considerably increasing the number of established trait loci. Thirty-four loci are novel associations with hearing loss of any form, and only one of the ten known hearing loci has a previously reported association with an ARHI-related trait. Gene sets from these loci are enriched in auditory processes such as synaptic activities, nervous system processes, inner ear morphology, and cognition, while genetic correlation analysis revealed strong positive correlations with multiple personality and psychological traits for the first time. Immunohistochemistry for protein localization in adult mouse cochlea implicate metabolic, sensory, and neuronal functions for NID2, CLRN2, and ARHGEF28. These results provide insight into the genetic landscape underlying ARHI, opening up novel therapeutic targets for further investigation. In a wider context, our study also highlights the viability of using self-report phenotypes for genetic discovery in very large samples when deep phenotyping is unavailable.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817556PMC
October 2019

Pleiotropic Meta-Analysis of Cognition, Education, and Schizophrenia Differentiates Roles of Early Neurodevelopmental and Adult Synaptic Pathways.

Am J Hum Genet 2019 08;105(2):334-350

Centre for Epidemiology, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester M139PL, United Kingdom; School of Healthcare Sciences, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom.

Susceptibility to schizophrenia is inversely correlated with general cognitive ability at both the phenotypic and the genetic level. Paradoxically, a modest but consistent positive genetic correlation has been reported between schizophrenia and educational attainment, despite the strong positive genetic correlation between cognitive ability and educational attainment. Here we leverage published genome-wide association studies (GWASs) in cognitive ability, education, and schizophrenia to parse biological mechanisms underlying these results. Association analysis based on subsets (ASSET), a pleiotropic meta-analytic technique, allowed jointly associated loci to be identified and characterized. Specifically, we identified subsets of variants associated in the expected ("concordant") direction across all three phenotypes (i.e., greater risk for schizophrenia, lower cognitive ability, and lower educational attainment); these were contrasted with variants that demonstrated the counterintuitive ("discordant") relationship between education and schizophrenia (i.e., greater risk for schizophrenia and higher educational attainment). ASSET analysis revealed 235 independent loci associated with cognitive ability, education, and/or schizophrenia at p < 5 × 10. Pleiotropic analysis successfully identified more than 100 loci that were not significant in the input GWASs. Many of these have been validated by larger, more recent single-phenotype GWASs. Leveraging the joint genetic correlations of cognitive ability, education, and schizophrenia, we were able to dissociate two distinct biological mechanisms-early neurodevelopmental pathways that characterize concordant allelic variation and adulthood synaptic pruning pathways-that were linked to the paradoxical positive genetic association between education and schizophrenia. Furthermore, genetic correlation analyses revealed that these mechanisms contribute not only to the etiopathogenesis of schizophrenia but also to the broader biological dimensions implicated in both general health outcomes and psychiatric illness.
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http://dx.doi.org/10.1016/j.ajhg.2019.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699140PMC
August 2019

Longitudinal change of sleep timing: association between chronotype and longevity in older adults.

Chronobiol Int 2019 09 22;36(9):1285-1300. Epub 2019 Jul 22.

a Division of Neuroscience & Experimental Psychology, School of Biological Sciences, The University of Manchester , Manchester , UK.

Evening-oriented sleep timing preferences have been associated with risk of diabetes, cardiovascular diseases, obesity, psychiatric disorders, and increased mortality. This research aims to explore the relationship between diurnal preferences (chronotype), daily habits, metabolic health, and mortality, using longitudinal data from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age (6375 participants at inception, recruited in the North of England) with a long follow-up period (up to 35.5 years). Mixed models were used to investigate the influence of aging, socio-demographic, and seasonal factors on sleep timing. Results show that sleep timing shifted towards earlier time with aging. Test seasons influence chronotype of older adults but working schedules challenge seasonality of sleep timing. Moreover, the season of birth may set chronotype in adulthood. Individual chronotype trajectories were clustered using latent class analysis and analyzed against metabolic health and mortality. We observed a higher risk of hypertension in the evening-type cluster compared to morning-type individuals (Odds ratio = 1.88, 95%CI = 1.02/3.47, = .04). Evening-type cluster was also associated with traits related to lower health such as reduced sport participation, increased risk of depression and psychoticism personality, late eating, and increased smoking and alcohol usage. Finally, Cox regression of proportional hazards was used to study the effects of chronotype on longevity after adjusting for sleep duration, age, gender, smoking, alcohol usage, general health, and social class. The survival analysis (82.6% censored by death) revealed that evening-type chronotype increased the likelihood of mortality (Hazard ratio = 1.15, 95%CI = 1.04/1.26, = .005). Taken together, chronotype is influenced by aging and seasonal effects. Evening-type preference may have detrimental outcomes for human well-being and longevity.
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http://dx.doi.org/10.1080/07420528.2019.1641111DOI Listing
September 2019

Longitudinal sleep efficiency in the elderly and its association with health.

J Sleep Res 2020 06 16;29(3):e12898. Epub 2019 Jul 16.

Division of Neuroscience and Experimental Psychology, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.

The relationships between older age and sleep efficiency have traditionally been assessed using cross-sectional studies that ignore changes within individuals as they age. This research examines the determinants of sleep efficiency, the heterogeneity in an individual's sleep efficiency trajectory across a period of up to 27 years in later life and its associations with health. The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age cohort (n = 6,375; age 42-94 years) was used in this study. Depression and health data were collected using self-report validated instruments (Cornell Medical Index, Beck Depression Inventory and Geriatric Depression Scale). Longitudinal sleep and sociodemographic data were collected using a study-specific self-report questionnaire. A mixed-effect model was performed for sleep efficiency with adjustments for time-invariant and time-variant predictors. Latent class analysis was used to demonstrate subgroups of sleep efficiency trajectories and associations between sleep efficiency clusters and health history of the participants were investigated. Older adults have decreased sleep efficiency over time, with 18.6% decline between 40 and 100 years of age. Three sleep efficiency trajectory clusters were identified: high (32%), medium (50%) and low sleep efficiency (18%). Belonging to the high sleep efficiency cluster was associated with having lower prevalence of hypertension, circulatory problems, general arthritis, breathing problems and recurrent episodes of depression compared to the low efficiency cluster. Overall, ageing decreases sleep efficiency. However, there are detectable subgroups of sleep efficiency that are related to prevalence of different diseases.
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http://dx.doi.org/10.1111/jsr.12898DOI Listing
June 2020

Dysregulation of BDNF in Prefrontal Cortex in Alzheimer's Disease.

J Alzheimers Dis 2019 ;69(4):1089-1097

Bioscience Research Centre, Manchester Metropolitan University, Manchester, UK.

Background: Brain-derived neurotrophic factor (BDNF) is essential for neurogenesis and has been implicated in Alzheimer's disease (AD). However, few studies have investigated together the epigenetic, transcriptional, and translational regulation of this peptide in the brain in relation to AD.

Objective: To investigate mechanisms underlying how BDNF is possibly dysregulated in the brain in relation to aging and AD neuropathology.

Methods: Prefrontal cortex tissues were acquired from the Manchester Brain Bank (N = 67). BDNF exon I, and exon IV-containing transcripts and total long 3' transcript gene expression were determined by quantitative PCR and bisulfite pyrosequencing was used to quantify DNA methylation within promoters I and IV. Protein concentrations were quantified via ELISA.

Results: BDNF exon IV and total long 3' isoform gene expression levels negatively associated with donor's age at death (IV: r = -0.291, p = 0.020; total: r = -0.354, p = 0.004). Expression of BDNF exon I- containing isoform was significantly higher in Met-carriers of the rs6265 variant, compared to Val-homozygotes, when accounting for donor ages (F = 6.455, p = 0.014). BDNF total long 3' transcript expression was significantly lower in those with early AD neuropathology, compared to those without any neuropathology (p = 0.021). There were no associations between BDNF promoter I and IV methylation or protein levels with ages, rs6265 genotype or AD neuropathology status.

Conclusion: Prefrontal cortex BDNF gene expression is associated with aging, rs6265 carrier status, and AD neuropathology in a variant-specific manner that seems to be independent of DNA methylation influences.
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http://dx.doi.org/10.3233/JAD-190049DOI Listing
September 2020

Author Correction: Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Nat Commun 2019 May 1;10(1):2068. Epub 2019 May 1.

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland.

Christina M. Lill, who contributed to analysis of data, was inadvertently omitted from the author list in the originally published version of this article. This has now been corrected in both the PDF and HTML versions of the article.
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http://dx.doi.org/10.1038/s41467-019-10160-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494826PMC
May 2019

Genetic influences on the variability of response to repetitive transcranial magnetic stimulation in human pharyngeal motor cortex.

Neurogastroenterol Motil 2019 07 29;31(7):e13612. Epub 2019 Apr 29.

Division of Diabetes, Endocrinology and Gastroenterology, Faculty of Biology, Medicine and Health, Centre for Gastrointestinal Sciences, School of Medical Sciences, The University of Manchester, Manchester, UK.

Background: Recent studies have reported substantial variability in response to repetitive transcranial magnetic stimulation (rTMS). We hypothesized that an individual's genetic predisposition may contribute to such variability in the pharyngeal motor cortex. This study aimed to investigate the response to 1 and 5 Hz rTMS paradigms on pharyngeal motor cortex in healthy participants and its relationship with genetic predisposition.

Methods: Forty-one healthy participants (25.4 ± 4.6 years old) received either or both 1 Hz (n = 39) and 5 Hz rTMS (n = 40) over pharyngeal motor cortex. Pharyngeal and thenar motor-evoked potentials were recorded at baseline and for 1 hour post-rTMS. The participants were then classified according to their response. The associations between rTMS response and gender, time of day of the stimulation, and eight prespecified single nucleotide polymorphisms (SNPs) were analyzed.

Key Results: There was no direction-specific response to either paradigm (1 Hz: F[3.69, 129.21] = 0.78, P = 0.56; 5 Hz: F[4.08, 146.85] = 1.38, P = 0.25). Only 13% of participants showed the expected bidirectional response (inhibition for 1 Hz and excitation for 5 Hz). Significant associations were found between response and COMT (1 Hz: P = 0.03) and DRD2 (1 Hz: P = 0.02; 5 Hz: P = 0.04) polymorphisms. Carriers of minor allele G from SNP rs6269 (COMT) were more likely to show inhibitory or excitatory outcomes after 1 Hz rTMS. By contrast, carriers of minor allele A from SNP rs1800497 (DRD2) were more likely to show no response to 1 Hz rTMS and inhibition after 5 Hz rTMS.

Conclusions & Inferences: Two SNPs from COMT and DRD2 genes may partially explain the response variability to rTMS in the pharyngeal motor system. Further research should focus on stratified approaches for neurostimulatory dysphagia treatment using rTMS.
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http://dx.doi.org/10.1111/nmo.13612DOI Listing
July 2019

Multi-Trait Analysis of GWAS and Biological Insights Into Cognition: A Response to Hill (2018).

Twin Res Hum Genet 2018 10 13;21(5):394-397. Epub 2018 Jul 13.

Department of Psychiatry,National and Kapodistrian University of Athens Medical School,Eginition Hospital,Athens,Greece.

Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88) presented a critique of our recently published paper in Cell Reports entitled 'Large-Scale Cognitive GWAS Meta-Analysis Reveals Tissue-Specific Neural Expression and Potential Nootropic Drug Targets' (Lam et al., Cell Reports, Vol. 21, 2017, 2597-2613). Specifically, Hill offered several interrelated comments suggesting potential problems with our use of a new analytic method called Multi-Trait Analysis of GWAS (MTAG) (Turley et al., Nature Genetics, Vol. 50, 2018, 229-237). In this brief article, we respond to each of these concerns. Using empirical data, we conclude that our MTAG results do not suffer from 'inflation in the FDR [false discovery rate]', as suggested by Hill (Twin Research and Human Genetics, Vol. 21, 2018, 84-88), and are not 'more relevant to the genetic contributions to education than they are to the genetic contributions to intelligence'.
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http://dx.doi.org/10.1017/thg.2018.46DOI Listing
October 2018

Genome-wide association meta-analysis in 269,867 individuals identifies new genetic and functional links to intelligence.

Nat Genet 2018 07 25;50(7):912-919. Epub 2018 Jun 25.

Laboratory of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.

Intelligence is highly heritable and a major determinant of human health and well-being. Recent genome-wide meta-analyses have identified 24 genomic loci linked to variation in intelligence, but much about its genetic underpinnings remains to be discovered. Here, we present a large-scale genetic association study of intelligence (n = 269,867), identifying 205 associated genomic loci (190 new) and 1,016 genes (939 new) via positional mapping, expression quantitative trait locus (eQTL) mapping, chromatin interaction mapping, and gene-based association analysis. We find enrichment of genetic effects in conserved and coding regions and associations with 146 nonsynonymous exonic variants. Associated genes are strongly expressed in the brain, specifically in striatal medium spiny neurons and hippocampal pyramidal neurons. Gene set analyses implicate pathways related to nervous system development and synaptic structure. We confirm previous strong genetic correlations with multiple health-related outcomes, and Mendelian randomization analysis results suggest protective effects of intelligence for Alzheimer's disease and ADHD and bidirectional causation with pleiotropic effects for schizophrenia. These results are a major step forward in understanding the neurobiology of cognitive function as well as genetically related neurological and psychiatric disorders.
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http://dx.doi.org/10.1038/s41588-018-0152-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6411041PMC
July 2018

Study of 300,486 individuals identifies 148 independent genetic loci influencing general cognitive function.

Nat Commun 2018 05 29;9(1):2098. Epub 2018 May 29.

Department of Psychology and Logopedics, Faculty of Medicine, University of Helsinki, Helsinki, 00014, Finland.

General cognitive function is a prominent and relatively stable human trait that is associated with many important life outcomes. We combine cognitive and genetic data from the CHARGE and COGENT consortia, and UK Biobank (total N = 300,486; age 16-102) and find 148 genome-wide significant independent loci (P < 5 × 10) associated with general cognitive function. Within the novel genetic loci are variants associated with neurodegenerative and neurodevelopmental disorders, physical and psychiatric illnesses, and brain structure. Gene-based analyses find 709 genes associated with general cognitive function. Expression levels across the cortex are associated with general cognitive function. Using polygenic scores, up to 4.3% of variance in general cognitive function is predicted in independent samples. We detect significant genetic overlap between general cognitive function, reaction time, and many health variables including eyesight, hypertension, and longevity. In conclusion we identify novel genetic loci and pathways contributing to the heritability of general cognitive function.
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http://dx.doi.org/10.1038/s41467-018-04362-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5974083PMC
May 2018
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