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Article ; Online: Generation Scotland participant survey on data collection [version 2; peer review

Rachel Edwards / Archie Campbell / David Porteous

Wellcome Open Research, Vol

2 approved]

2019 Volume 4

Abstract: Background: Generation Scotland (GS) is a population and family-based study of genetic and environmental health determinants. Recruitment to the Scottish Family Health Study component of GS took place between 2006-2011. Participants were aged 18 or over ... ...

Abstract	Background: Generation Scotland (GS) is a population and family-based study of genetic and environmental health determinants. Recruitment to the Scottish Family Health Study component of GS took place between 2006-2011. Participants were aged 18 or over and consented to genetic studies, linkage to health records and recontact. Several recontact exercises have been successfully conducted aimed at a) recruitment to embedded or partner studies and b) the collection of additional data. As the cohort matures in age, we were interested in surveying attitudes to potential new approaches to data collection and recruitment. Methods: A ten-question online survey was sent to those participants who provided an email address. Results: We report a high level of positive responses to encouraging relatives to participate, to remote data and sample collection and for research access to stored newborn dried blood spots. Conclusions: The majority of current and prospective GS participants are likely to respond positively to future requests for remote data and sample collection.
Keywords	Medicine ; R ; Science ; Q
Subject code	333
Language	English
Publishing date	2019-12-01T00:00:00Z
Publisher	Wellcome
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair

Kitty Sherwood / Joseph C. Ward / Ignacio Soriano / Lynn Martin / Archie Campbell / Raheleh Rahbari / Ioannis Kafetzopoulos / Duncan Sproul / Andrew Green / Julian R. Sampson / Alan Donaldson / Kai-Ren Ong / Karl Heinimann / Maartje Nielsen / Huw Thomas / Andrew Latchford / Claire Palles / Ian Tomlinson

Nature Communications, Vol 14, Iss 1, Pp 1-

2023 Volume 10

Abstract: Abstract DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or ... ...

Abstract	Abstract DNA repair defects underlie many cancer syndromes. We tested whether de novo germline mutations (DNMs) are increased in families with germline defects in polymerase proofreading or base excision repair. A parent with a single germline POLE or POLD1 mutation, or biallelic MUTYH mutations, had 3-4 fold increased DNMs over sex-matched controls. POLE had the largest effect. The DNMs carried mutational signatures of the appropriate DNA repair deficiency. No DNM increase occurred in offspring of MUTYH heterozygous parents. Parental DNA repair defects caused about 20–150 DNMs per child, additional to the ~60 found in controls, but almost all extra DNMs occurred in non-coding regions. No increase in post-zygotic mutations was detected, excepting a child with bi-allelic MUTYH mutations who was excluded from the main analysis; she had received chemotherapy and may have undergone oligoclonal haematopoiesis. Inherited DNA repair defects associated with base pair-level mutations increase DNMs, but phenotypic consequences appear unlikely.
Keywords	Science ; Q
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Blood-based epigenome-wide analyses of 19 common disease states

Robert F Hillary / Daniel L McCartney / Hannah M Smith / Elena Bernabeu / Danni A Gadd / Aleksandra D Chybowska / Yipeng Cheng / Lee Murphy / Nicola Wrobel / Archie Campbell / Rosie M Walker / Caroline Hayward / Kathryn L Evans / Andrew M McIntosh / Riccardo E Marioni

PLoS Medicine, Vol 20, Iss 7, p e

A longitudinal, population-based linked cohort study of 18,413 Scottish individuals.

2023 Volume 1004247

Abstract: Background DNA methylation is a dynamic epigenetic mechanism that occurs at cytosine-phosphate-guanine dinucleotide (CpG) sites. Epigenome-wide association studies (EWAS) investigate the strength of association between methylation at individual CpG sites ...

Abstract	Background DNA methylation is a dynamic epigenetic mechanism that occurs at cytosine-phosphate-guanine dinucleotide (CpG) sites. Epigenome-wide association studies (EWAS) investigate the strength of association between methylation at individual CpG sites and health outcomes. Although blood methylation may act as a peripheral marker of common disease states, previous EWAS have typically focused only on individual conditions and have had limited power to discover disease-associated loci. This study examined the association of blood DNA methylation with the prevalence of 14 disease states and the incidence of 19 disease states in a single population of over 18,000 Scottish individuals. Methods and findings DNA methylation was assayed at 752,722 CpG sites in whole-blood samples from 18,413 volunteers in the family-structured, population-based cohort study Generation Scotland (age range 18 to 99 years). EWAS tested for cross-sectional associations between baseline CpG methylation and 14 prevalent disease states, and for longitudinal associations between baseline CpG methylation and 19 incident disease states. Prevalent cases were self-reported on health questionnaires at the baseline. Incident cases were identified using linkage to Scottish primary (Read 2) and secondary (ICD-10) care records, and the censoring date was set to October 2020. The mean time-to-diagnosis ranged from 5.0 years (for chronic pain) to 11.7 years (for Coronavirus Disease 2019 (COVID-19) hospitalisation). The 19 disease states considered in this study were selected if they were present on the World Health Organisation's 10 leading causes of death and disease burden or included in baseline self-report questionnaires. EWAS models were adjusted for age at methylation typing, sex, estimated white blood cell composition, population structure, and 5 common lifestyle risk factors. A structured literature review was also conducted to identify existing EWAS for all 19 disease states tested. The MEDLINE, Embase, Web of Science, and preprint servers were ...
Keywords	Medicine ; R
Subject code	610
Language	English
Publishing date	2023-07-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Author Correction

Nature Communications, Vol 14, Iss 1, Pp 1-

Germline de novo mutations in families with Mendelian cancer syndromes caused by defects in DNA repair

2023 Volume 1

Keywords	Science ; Q
Language	English
Publishing date	2023-06-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Integration of datasets for individual prediction of DNA methylation-based biomarkers

Charlotte Merzbacher / Barry Ryan / Thibaut Goldsborough / Robert F. Hillary / Archie Campbell / Lee Murphy / Andrew M. McIntosh / David Liewald / Sarah E. Harris / Allan F. McRae / Simon R. Cox / Timothy I. Cannings / Catalina A. Vallejos / Daniel L. McCartney / Riccardo E. Marioni

Genome Biology, Vol 24, Iss 1, Pp 1-

2023 Volume 12

Abstract: Abstract Background Epigenetic scores (EpiScores) can provide biomarkers of lifestyle and disease risk. Projecting new datasets onto a reference panel is challenging due to separation of technical and biological variation with array data. Normalisation ... ...

Abstract	Abstract Background Epigenetic scores (EpiScores) can provide biomarkers of lifestyle and disease risk. Projecting new datasets onto a reference panel is challenging due to separation of technical and biological variation with array data. Normalisation can standardise data distributions but may also remove population-level biological variation. Results We compare two birth cohorts (Lothian Birth Cohorts of 1921 and 1936 — nLBC1921 = 387 and nLBC1936 = 498) with blood-based DNA methylation assessed at the same chronological age (79 years) and processed in the same lab but in different years and experimental batches. We examine the effect of 16 normalisation methods on a novel BMI EpiScore (trained in an external cohort, n = 18,413), and Horvath’s pan-tissue DNA methylation age, when the cohorts are normalised separately and together. The BMI EpiScore explains a maximum variance of R 2=24.5% in BMI in LBC1936 (SWAN normalisation). Although there are cross-cohort R 2 differences, the normalisation method makes a minimal difference to within-cohort estimates. Conversely, a range of absolute differences are seen for individual-level EpiScore estimates for BMI and age when cohorts are normalised separately versus together. While within-array methods result in identical EpiScores whether a cohort is normalised on its own or together with the second dataset, a range of differences is observed for between-array methods. Conclusions Normalisation methods returning similar EpiScores, whether cohorts are analysed separately or together, will minimise technical variation when projecting new data onto a reference panel. These methods are important for cases where raw data is unavailable and joint normalisation of cohorts is computationally expensive.
Keywords	DNA methylation ; Prediction ; Biomarker ; Biology (General) ; QH301-705.5 ; Genetics ; QH426-470
Subject code	310
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of epigenome-wide DNA methylation differences between carriers of APOE ε4 and APOE ε2 alleles

Rosie M. Walker / Kadi Vaher / Mairead L. Bermingham / Stewart W. Morris / Andrew D. Bretherick / Yanni Zeng / Konrad Rawlik / Carmen Amador / Archie Campbell / Chris S. Haley / Caroline Hayward / David J. Porteous / Andrew M. McIntosh / Riccardo E. Marioni / Kathryn L. Evans

Genome Medicine, Vol 13, Iss 1, Pp 1-

2021 Volume 14

Abstract: Abstract Background The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 ... ...

Abstract	Abstract Background The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease, whilst the ε2 allele confers protection. Previous studies report differential DNA methylation of APOE between ε4 and ε2 carriers, but associations with epigenome-wide methylation have not previously been characterised. Methods Using the EPIC array, we investigated epigenome-wide differences in whole blood DNA methylation patterns between Alzheimer’s disease-free APOE ε4 (n = 2469) and ε2 (n = 1118) carriers from the two largest single-cohort DNA methylation samples profiled to date. Using a discovery, replication and meta-analysis study design, methylation differences were identified using epigenome-wide association analysis and differentially methylated region (DMR) approaches. Results were explored using pathway and methylation quantitative trait loci (meQTL) analyses. Results We obtained replicated evidence for DNA methylation differences in a ~ 169 kb region, which encompasses part of APOE and several upstream genes. Meta-analytic approaches identified DNA methylation differences outside of APOE: differentially methylated positions were identified in DHCR24, LDLR and ABCG1 (2.59 × 10−100 ≤ P ≤ 2.44 × 10−8) and DMRs were identified in SREBF2 and LDLR (1.63 × 10−4 ≤ P ≤ 3.01 × 10−2). Pathway and meQTL analyses implicated lipid-related processes and high-density lipoprotein cholesterol was identified as a partial mediator of the methylation differences in ABCG1 and DHCR24. Conclusions APOE ε4 vs. ε2 carrier status is associated with epigenome-wide methylation differences in the blood. The loci identified are located in trans as well as cis to APOE and implicate genes involved in lipid homeostasis.
Keywords	Alzheimer’s disease ; APOE ; Apolipoprotein E ; DNA methylation ; Cholesterol ; Lipids ; Medicine ; R ; Genetics ; QH426-470
Subject code	570 ; 310
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	BMC
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Complex trait methylation scores in the prediction of major depressive disorder

Miruna C. Barbu / Carmen Amador / Alex S.F. Kwong / Xueyi Shen / Mark J. Adams / David M. Howard / Rosie M. Walker / Stewart W. Morris / Josine L. Min / Chunyu Liu / Jenny van Dongen / Mohsen Ghanbari / Caroline Relton / David J. Porteous / Archie Campbell / Kathryn L. Evans / Heather C. Whalley / Andrew M. McIntosh

EBioMedicine, Vol 79, Iss , Pp 104000- (2022)

2022

Abstract: Summary: Background: DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with ...

Abstract	Summary: Background: DNA methylation (DNAm) is associated with time-varying environmental factors that contribute to major depressive disorder (MDD) risk. We sought to test whether DNAm signatures of lifestyle and biochemical factors were associated with MDD to reveal dynamic biomarkers of MDD risk that may be amenable to lifestyle interventions. Methods: Here, we calculated methylation scores (MS) at multiple p-value thresholds for lifestyle (BMI, smoking, alcohol consumption, and educational attainment) and biochemical (high-density lipoprotein (HDL) and total cholesterol) factors in Generation Scotland (GS) (N=9,502) and in a replication cohort (ALSPACadults, N=565), using CpG sites reported in previous well-powered methylome-wide association studies. We also compared their predictive accuracy for MDD to a MDD MS in an independent GS sub-sample (N=4,432). Findings: Each trait MS was significantly associated with its corresponding phenotype in GS (βrange=0.089–1.457) and in ALSPAC (βrange=0.078–2.533). Each MS was also significantly associated with MDD before and after adjustment for its corresponding phenotype in GS (βrange=0.053–0.145). After accounting for relevant lifestyle factors, MS for educational attainment (β=0.094) and alcohol consumption (MSp-value<0.01–0.5; βrange=-0.069–0.083) remained significantly associated with MDD in GS. Smoking (AUC=0.569) and educational attainment (AUC=0.585) MSs could discriminate MDD from controls better than the MDD MS (AUC=0.553) in the independent GS sub-sample. Analyses implicating MDD did not replicate across ALSPAC, although the direction of effect was consistent for all traits when adjusting for the MS corresponding phenotypes. Interpretation: We showed that lifestyle and biochemical MS were associated with MDD before and after adjustment for their corresponding phenotypes (pnominal<0.05), but not when smoking, alcohol consumption, and BMI were also included as covariates. MDD results did not replicate in the smaller, female-only independent ALSPAC cohort ...
Keywords	DNA methylation ; Methylation score ; Environmental factors ; Major depressive disorder ; Generation Scotland ; Avon longitudinal study of parents and children ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	310
Language	English
Publishing date	2022-05-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Electronic health record and genome-wide genetic data in Generation Scotland participants [version 1; referees

Shona M. Kerr / Archie Campbell / Jonathan Marten / Veronique Vitart / Andrew M McIntosh / David J. Porteous / Caroline Hayward

Wellcome Open Research, Vol

2 approved, 1 approved with reservations]

2017 Volume 2

Abstract: This article provides the first detailed demonstration of the research value of the Electronic Health Record (EHR) linked to research data in Generation Scotland Scottish Family Health Study (GS:SFHS) participants, together with how to access this data. ... ...

Abstract	This article provides the first detailed demonstration of the research value of the Electronic Health Record (EHR) linked to research data in Generation Scotland Scottish Family Health Study (GS:SFHS) participants, together with how to access this data. The structured, coded variables in the routine biochemistry, prescribing and morbidity records, in particular, represent highly valuable phenotypic data for a genomics research resource. Access to a wealth of other specialized datasets, including cancer, mental health and maternity inpatient information, is also possible through the same straightforward and transparent application process. The EHR linked dataset is a key component of GS:SFHS, a biobank conceived in 1999 for the purpose of studying the genetics of health areas of current and projected public health importance. Over 24,000 adults were recruited from 2006 to 2011, with broad and enduring written informed consent for biomedical research. Consent was obtained from 23,603 participants for GS:SFHS study data to be linked to their Scottish National Health Service (NHS) records, using their Community Health Index number. This identifying number is used for NHS Scotland procedures (registrations, attendances, samples, prescribing and investigations) and allows healthcare records for individuals to be linked across time and location. Here, we describe the NHS EHR dataset on the sub-cohort of 20,032 GS:SFHS participants with consent and mechanism for record linkage plus extensive genetic data. Together with existing study phenotypes, including family history and environmental exposures, such as smoking, the EHR is a rich resource of real world data that can be used in research to characterise the health trajectory of participants, available at low cost and a high degree of timeliness, matched to DNA, urine and serum samples and genome-wide genetic information.
Keywords	Data Sharing ; Health Systems & Services Research ; Social & Behavioral Determinants of Health ; Statistical Methodologies & Health Informatics ; Medicine ; R ; Science ; Q
Subject code	360
Language	English
Publishing date	2017-09-01T00:00:00Z
Publisher	Wellcome
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Assessment of dried blood spots for DNA methylation profiling [version 1; peer review

Rosie M. Walker / Louise MacGillivray / Sarah McCafferty / Nicola Wrobel / Lee Murphy / Shona M. Kerr / Stewart W. Morris / Archie Campbell / Andrew M. McIntosh / David J. Porteous / Kathryn L. Evans

Wellcome Open Research, Vol

2 approved]

2019 Volume 4

Abstract: Background: DNA methylation reflects health-related environmental exposures and genetic risk, providing insights into aetiological mechanisms and potentially predicting disease onset, progression and treatment response. An increasingly recognised need ... ...

Abstract	Background: DNA methylation reflects health-related environmental exposures and genetic risk, providing insights into aetiological mechanisms and potentially predicting disease onset, progression and treatment response. An increasingly recognised need for large-scale, longitudinally-profiled samples collected world-wide has made the development of efficient and straightforward sample collection and storage procedures a pressing issue. An alternative to the low-temperature storage of EDTA tubes of venous blood samples, which are frequently the source of the DNA used in such studies, is to collect and store at room temperature blood samples using purpose built filter paper, such as Whatman FTA® cards. Our goal was to determine whether DNA stored in this manner can be used to generate DNA methylation profiles comparable to those generated using blood samples frozen in EDTA tubes. Methods: DNA methylation profiles were obtained from matched EDTA tube and Whatman FTA® card whole-blood samples from 62 Generation Scotland: Scottish Family Health Study participants using the Infinium HumanMethylation450 BeadChip. Multiple quality control procedures were implemented, the relationship between the two sample types assessed, and epigenome-wide association studies (EWASs) performed for smoking status, age and the interaction between these variables and sample storage method. Results: Dried blood spot (DBS) DNA methylation profiles were of good quality and DNA methylation profiles from matched DBS and EDTA tube samples were highly correlated (mean r = 0.991) and could distinguish between participants. EWASs replicated established associations for smoking and age, with no evidence for moderation by storage method. Conclusions: Our results support the use of Whatman FTA® cards for collecting and storing blood samples for DNA methylation profiling. This approach is likely to be particularly beneficial for large-scale studies and those carried out in areas where freezer access is limited. Furthermore, our results will inform ...
Keywords	Medicine ; R ; Science ; Q
Subject code	310
Language	English
Publishing date	2019-03-01T00:00:00Z
Publisher	Wellcome
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Lifestyle and Genetic Factors Modify Parent-of-Origin Effects on the Human Methylome

Yanni Zeng / Carmen Amador / Chenhao Gao / Rosie M. Walker / Stewart W. Morris / Archie Campbell / Azra Frkatović / Rebecca A Madden / Mark J. Adams / Shuai He / Andrew D. Bretherick / Caroline Hayward / David J. Porteous / James F. Wilson / Kathryn L. Evans / Andrew M. McIntosh / Pau Navarro / Chris S. Haley

EBioMedicine, Vol 74, Iss , Pp 103730- (2021)

2021

Abstract: Background: parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic ... ...

Abstract	Background: parent-of-origin effects (POE) play important roles in complex disease and thus understanding their regulation and associated molecular and phenotypic variation are warranted. Previous studies mainly focused on the detection of genomic regions or phenotypes regulated by POE. Understanding whether POE may be modified by environmental or genetic exposures is important for understanding of the source of POE-associated variation, but only a few case studies addressing modifiable POE exist. Methods: in order to understand this high order of POE regulation, we screened 101 genetic and environmental factors such as ‘predicted mRNA expression levels’ of DNA methylation/imprinting machinery genes and environmental exposures. POE-mQTL-modifier interaction models were proposed to test the potential of these factors to modify POE at DNA methylation using data from Generation Scotland: The Scottish Family Health Study(N=2315). Findings: a set of vulnerable/modifiable POE-CpGs were identified (modifiable-POE-regulated CpGs, N=3). Four factors, ‘lifetime smoking status’ and ‘predicted mRNA expression levels’ of TET2, SIRT1 and KDM1A, were found to significantly modify the POE on the three CpGs in both discovery and replication datasets. We further identified plasma protein and health-related phenotypes associated with the methylation level of one of the identified CpGs. Interpretation: the modifiable POE identified here revealed an important yet indirect path through which genetic background and environmental exposures introduce their effect on DNA methylation, motivating future comprehensive evaluation of the role of these modifiers in complex diseases. Funding: NSFC (81971270),H2020-MSCA-ITN(721815), Wellcome (204979/Z/16/Z,104036/Z/14/Z), MRC (MC_UU_00007/10, MC_PC_U127592696), CSO (CZD/16/6,CZB/4/276, CZB/4/710), SFC (HR03006), EUROSPAN (LSHG-CT-2006-018947), BBSRC (BBS/E/D/30002276), SYSU, Arthritis Research UK, NHLBI, NIH.
Keywords	parent-of-origin effect ; DNA methylation ; interaction (modification) effect ; mQTL ; DNA methylation machinery genes ; smoking ; Medicine ; R ; Medicine (General) ; R5-920
Subject code	570
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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