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Caroline Hayward

Publications and source records attributed to Caroline Hayward.

At least 19 recordsLinked to original sources
PubMed2025

Gene-environment interaction analysis in atopic eczema: evidence from large population datasets and modelling in vitro.

BACKGROUND: Environmental factors play a role in the pathogenesis of complex traits including atopic eczema (AE) and a greater understanding of gene-environment interactions (G*E) is needed to define pathomechanisms for disease prevention. We analysed data from 16 European studies to test for interaction between the 24 most significant AE-associated loci identified from genome-wide association studies and 18 early-life environmental factors. We tested for replication using a further 10 studies and in vitro modelling to independently assess findings. RESULTS: The discovery analysis showed suggestive evidence for interaction (p<0.05) between 7 environmental factors (antibiotic use, cat ownership, dog ownership, breastfeeding, elder sibling, smoking and washing practices) and at least one established variant for AE, 14 interactions in total (maxN=25,339). In replication analysis (maxN=252,040) dog exposure*rs10214237 (on chromosome 5p13.2 near IL7R) was nominally significant (ORinteraction=0.91 [0.83-0.99] P=0.025), with a risk effect of the T allele observed only in those not exposed to dogs. A similar interaction with rs10214237 was observed for siblings in the discovery analysis (ORinteraction=0.84[0.75-0.94] P=0.003), but replication analysis was under-powered ORinteraction=1.09[0.82-1.46]). Rs10214237 homozygous risk genotype is associated with lower IL-7R expression in human keratinocytes, and dog exposure modelled in vitro showed a differential response according to rs10214237 genotype. CONCLUSIONS: Interaction analysis and functional assessment provide evidence that early-life dog exposure may modify the genetic effect of rs10214237 on AE via IL7R, supporting observational epidemiology showing a protective effect for dog ownership. The lack of evidence for other G*E studied here implies that only weak effects are likely to occur.

Atopic eczema↗
PubMed2025

Separating direct, indirect and parent-of-origin genetic effects in the human population.

Here, we present a novel approach to estimate the degree to which the phenotypic effect of a DNA locus is attributable to four components: alleles in the child (direct genetic effects), alleles in the mother and the father (indirect genetic effects), or is dependent upon the parent from which it is inherited (parent-of-origin, PofO effects). Applying our model, JODIE, to 30,000 child-mother-father trios with phased DNA information from the Estonian Biobank (EstBB) and the Norwegian Mother, Father, Child Cohort (MoBa), we jointly estimate the phenotypic variance attributable to these four effects unbiased of assortative mating (AM) for height, body mass index (BMI) and childhood educational test score (EA). For all three traits, direct effects make the largest contribution to the genetic effect variance. But we find that parental indirect genetic effects make an equivalent combined contribution, and that there is a non-zero PofO effect variance for all traits. We calculate the heritability that would be obtained at the population-level in the absence of AM for common DNA loci, and show that the proportional contribution of direct effects to these heritability values can be calculated as 64.0% for EA in MoBa, 77.1% and 63.4% for height in MoBa and EstBB, and 81.2% and 88.0% for BMI in MoBa and EstBB. Additionally, using within-family genome-wide association testing, we identify 276 independently associated DNA regions that replicate across two additional biobanks, which all show a genotype-phenotype relationship that reflects an interplay of direct, indirect and PofO effects. Determining how direct, parental and PofO genetic effects combine across loci genome-wide to influence human phenotypic variation requires joint modeling of parental and child genotypes alongside the parental origin of loci and here, we make the first attempt to do this in the human population.

EstBB↗
PubMed2025

An Updated Polygenic Index Repository: Expanded Phenotypes, New Cohorts, and Improved Causal Inference.

Polygenic indexes (PGIs) - DNA-based predictors of individual phenotypes - have become essential tools across biomedical and social sciences. We introduce Version 2 of the Polygenic Index Repository, which expands phenotype coverage from 47 to 61, increases the number of participating datasets from 11 to 20, and adopts a more consistent and improved methodology for PGI construction. For 16 phenotypes, we leverage summary statistics from an updated GWAS meta-analysis with greater statistical power compared to the original release, thereby improving the PGI's predictive power. To improve power for family-based analyses, we provide imputed parental PGIs in all datasets with first-degree relatives and offer a framework for interpreting results from analyses that control for parental PGIs. We illustrate the utility of parental PGIs using two applications: (1) comparing PGI associations with and without parental PGI controls for all phenotypes in two Repository datasets with family data, and (2) for BMI and diastolic blood pressure, exploring the contribution of causal versus non-causal components of PGI associations to the imperfect portability of PGIs across subgroups within a genetic ancestry. Collectively, the updates enhance predictive performance, broaden the Repository's scope, and introduce novel resources that reduce confounding bias and improve interpretability.

Journal Article↗
PubMed2024

Blood-based epigenome-wide analyses of chronic low-grade inflammation across diverse population cohorts.

Chronic inflammation is a hallmark of age-related disease states. The effectiveness of inflammatory proteins including C-reactive protein (CRP) in assessing long-term inflammation is hindered by their phasic nature. DNA methylation (DNAm) signatures of CRP may act as more reliable markers of chronic inflammation. We show that inter-individual differences in DNAm capture 50% of the variance in circulating CRP (N&#xa0;= 17,936, Generation Scotland). We develop a series of DNAm predictors of CRP using state-of-the-art algorithms. An elastic-net-regression-based predictor outperformed competing methods and explained 18% of phenotypic variance in the Lothian Birth Cohort of 1936 (LBC1936) cohort, doubling that of existing DNAm predictors. DNAm predictors performed comparably in four additional test cohorts (Avon Longitudinal Study of Parents and Children, Health for Life in Singapore, Southall and Brent Revisited, and LBC1921), including for individuals of diverse genetic ancestry and different age groups. The best-performing predictor surpassed assay-measured CRP and a genetic score in its associations with 26 health outcomes. Our findings forge new avenues for assessing chronic low-grade inflammation in diverse populations.

Humans↗
PubMed2008

Runs of homozygosity in European populations.

Estimating individual genome-wide autozygosity is important both in the identification of recessive disease variants via homozygosity mapping and in the investigation of the effects of genome-wide homozygosity on traits of biomedical importance. Approaches have tended to involve either single-point estimates or rather complex multipoint methods of inferring individual autozygosity, all on the basis of limited marker data. Now, with the availability of high-density genome scans, a multipoint, observational method of estimating individual autozygosity is possible. Using data from a 300,000 SNP panel in 2618 individuals from two isolated and two more-cosmopolitan populations of European origin, we explore the potential of estimating individual autozygosity from data on runs of homozygosity (ROHs). Termed F(roh), this is defined as the proportion of the autosomal genome in runs of homozygosity above a specified length. Mean F(roh) distinguishes clearly between subpopulations classified in terms of grandparental endogamy and population size. With the use of good pedigree data for one of the populations (Orkney), F(roh) was found to correlate strongly with the inbreeding coefficient estimated from pedigrees (r = 0.86). Using pedigrees to identify individuals with no shared maternal and paternal ancestors in five, and probably at least ten, generations, we show that ROHs measuring up to 4 Mb are common in demonstrably outbred individuals. Given the stochastic variation in ROH number, length, and location and the fact that ROHs are important whether ancient or recent in origin, approaches such as this will provide a more useful description of genomic autozygosity than has hitherto been possible.

Adolescent↗
PubMed2007

Effects of genome-wide heterozygosity on a range of biomedically relevant human quantitative traits.

The dramatic changes in human population structure over the last 200 years have resulted in significant levels of outbreeding, which, in turn, is predicted to lead to increased levels of individual genetic diversity (genome-wide heterozygosity, h). To investigate possible effects of these large demographic changes on global health, we studied the effect of h, measured as relative heterozygosity, h(R), on 15 disease-related traits in four groups of individuals with widely differing ancestral histories (ranging from outbred to inbred) from the Dalmatian islands in Croatia. Higher levels of h(R), estimated using 1184 STR/indel markers, were found in the outbred group (P < 0.0001) and were associated with lower blood pressure (BP) and total/LDL cholesterol (P = 0.01 and 0.01, respectively) after controlling for other factors, with BP showing a strong sex effect (males P > 0.5 and females P = 0.002). These findings, if replicated, suggest that h(R) be considered as a genetic risk factor in genetic epidemiological studies on common disease traits. They are consistent with the well-known effects of heterosis (hybrid vigour) described when outcrossing animals and plants. Outbreeding resulting from urbanization and migration from traditional population subgroups may be leading to increasing h(R) and may have beneficial effects on a range of traits associated with human health and disease. Other traits, such as age at menarche, IQ and lifespan, which have been changing during the decades of urbanization, may also have been influenced by demographic factors.

Age Factors↗
PubMed2006

Disease mechanisms in late-onset retinal macular degeneration associated with mutation in C1QTNF5.

Late-onset retinal macular degeneration (L-ORMD) is an autosomal dominant condition resembling age-related macular degeneration (AMD) in which a key pathological feature is a thick extracellular sub-retinal pigment epithelial (RPE) deposit. L-ORMD is caused by mutation in the C1QTNF5 (CTRP5) short-chain collagen gene, but the disease mechanism is unknown. Here, we first show that wild-type C1QTNF5 is secreted, whereas mutant C1QTNF5 is misfolded and retained within the endoplasmic reticulum (ER). Secondly, the ER retained mutant protein has a shorter half-life than wild-type C1QTNF5 and is preferentially degraded by proteasomes. Thirdly, C1QTNF5 is shown to interact with the membrane-type frizzled related protein (MFRP), on the basis of yeast two-hybrid, protein pull-down and co-immunoprecipitation assays and RPE co-localization. These data suggest that L-ORMD is due to insufficient levels of secreted C1QTNF5, compromised RPE cell function resulting from ER retention of the mutant protein or both mechanisms.

Age of Onset↗
PubMed2006

3000 years of solitude: extreme differentiation in the island isolates of Dalmatia, Croatia.

Communities with increased shared ancestry represent invaluable tools for genetic studies of complex traits. "1001 Dalmatians" research program collects biomedical information for genetic epidemiological research from multiple small isolated populations ('metapopulation') in the islands of Dalmatia, Croatia. Random samples of 100 individuals from 10 small island settlements (n<2000 inhabitants) were collected in 2002 and 2003. These island communities were carefully chosen to represent a wide range of distinct and well-documented demographic histories. Here, we analysed their genetic make-up using 26 short tandem repeat (STR) markers, at least 5 cM apart. We found a very high level of differentiation between most of these island communities based on Wright's fixation indexes, even within the same island. The model-based clustering algorithm, implemented in STRUCTURE, defined six clusters with very distinct genetic signatures, four of which corresponded to single villages. The extent of background LD, assessed with eight linked markers on Xq13-21, paralleled the extent of differentiation and was also very high in most of the populations under study. For each population, demographic history was characterised and 12 "demographic history" variables were tentatively defined. Following stepwise regression, the demographic history variable that most significantly predicted the extent of LD was the proportion of locally born grandparents. Strong isolation and endogamy are likely to be the main forces maintaining this highly structured overall population.

Cluster Analysis↗
PubMed2006

Historic exposure to plague and present-day frequency of CCR5del32 in two isolated island communities of Dalmatia, Croatia.

AIM: To assess the frequency of deletion of 32 base pairs in a CCR5 gene, shown to confer resistance to HIV infection, in two isolated island communities of Dalmatia, Croatia, with different histories of exposure to (plague) during the medieval period and beyond. METHODS: Random samples of 100 individuals from highly isolated communities of Lopar (island of Rab) and Komiza (island of Vis) were selected in 2002 and their DNA was extracted. An extremely high level of 3-generational endogamy was found in both communities (98% and 91%, respectively), indicating very limited gene flow, which was confirmed by available historic records. The two settlements also differed in their historic exposure to plague: between 1449 and 1456, Lopar was decimated by plague, while Komiza remained unaffected. Genotyping of the CCR5 polymorphism was performed using the polymerase chain reaction (PCR) method with primers flanking the region containing 32-bp deletion. RESULTS: The frequency of CCR5del32 in Lopar was 6.0% and in Komiza 1.5% (P=0.037). A previous study in 303 random Croatian blood donors showed a frequency of CCR5 32bp deletion of 7.1%. CONCLUSION: This study does not rule out the possible role of plague in positive selection at CCR5del32. However, analyses of further neighboring isolated island communities need to be made in order to provide more substantial support for this hypothesis.

Croatia↗
PubMed2005

Polymorphisms in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1) and lifetime cognitive change.

A rare polymorphism in the gene encoding 11B-hydroxysteroid dehydrogenase type 1 (HSD11B1: rs846911-C/A) has been associated with an increased risk of Alzheimer's disease. We tested the hypothesis that this and 2 other HSD11B1 polymorphisms (rs12086634-G/T and rs846910-A/G) were associated with lifetime cognitive change in humans. Subjects were 194 participants of the Scottish Mental Survey of 1932 who took the same well-validated mental test at age 11 and age 79. The subjects represented the highest and lowest quintiles with respect to cognitive decline between ages 11 and 79. Despite having non-significantly different IQs at age 11, by age 79 the groups had mean (S.D.) IQs of 80.3 (14.1) and 109.6 (9.1), respectively (p<.001). The polymorphism rs846911-C/A was absent from both groups. There were no significant differences in the frequency of polymorphisms of rs12086634-G/T (p=.91) and rs846910-A/G (p=.90) between the groups. We conclude that these variants in HSD11B1 are not significant contributors to the range of cognitive ageing examined here.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗
PubMed2005

Genetic influences on oxidative stress and their association with normal cognitive ageing.

Oxidative stress is hypothesised to play a major role in ageing processes. Reactive oxygen species produced during normal aerobic metabolism damage cellular macromolecules. The brain is particularly susceptible to oxidative stress due to its high rate of aerobic metabolism. We hypothesised that polymorphisms in genes contributing to antioxidant defences are associated with variation in normal cognitive ageing in the absence of dementia. We examined associations between two SNPs (rs2073495 and rs743658) in Lactotransferrin (LTF), a gene involved in iron absorption, and the common M129V SNP in the prion protein gene, PRNP (rs1799990), with cognitive ability and cognitive ageing in a cohort of non-demented individuals born in 1921. All had cognitive ability measured at age 11 in the Scottish Mental Survey of 1932, and again at age 79. No association was identified with LTF. PRNP M129V was significantly related to Moray House Test (MHT) IQ scores at age 79, adjusted for sex and age 11 IQ (p=0.006). Individuals homozygous for the methionine allele performed significantly better than heterozygotes. This study supports the hypothesis that genetic variations in antioxidant defence genes, specifically PRNP, are important influences on the trajectory of normal cognitive ageing. An interaction between PRNP and klotho (KL) genotypes was also identified (p=0.015), highlighting the importance of analysing gene interactions when investigating associations with quantitative traits.

Aged↗
PubMed2005

The functional COMT polymorphism, Val 158 Met, is associated with logical memory and the personality trait intellect/imagination in a cohort of healthy 79 year olds.

A polymorphism (Val 158 Met) in the gene for catechol-O-methyl transferase (COMT) was previously associated with differences in cognitive ability and personality. Here we examine associations between this polymorphism and cognitive ability, cognitive aging, personality and mood in 460 relatively healthy people born in 1921. All had cognitive ability measured at age 11 in the Scottish Mental Survey of 1932, and again at age 79. COMT genotype was not associated with childhood IQ. At age 79, COMT genotype was significantly related to differences in verbal declarative memory (scores on the Logical Memory test; p=0.028) and to scores on the personality trait of intellect/imagination (p=0.023), adjusted for sex and childhood IQ. In both cases the Val/Met heterozygotes had higher scores than both homozygous groups. There were trends toward the heterozygotes having higher scores on the personality traits of agreeableness and conscientiousness. The effect of COMT genotype on Logical Memory scores was independent of the effect of APOE genotype, and similar in effect size. Therefore, COMT genotype may contribute to differences in normal cognitive aging and to differences in some of the major personality traits in old age.

Aged↗
PubMed2005

Increased level of linkage disequilibrium in rural compared with urban communities: a factor to consider in association-study design.

Few studies have investigated genetic differentiation within nonisolate European populations, despite the initiation of large national sample collections such as U.K. Biobank. Here, we used short tandem repeat markers to explore fine-scale genetic structure and to examine the extent of linkage disequilibrium (LD) within national subpopulations. We studied 955 unrelated individuals of local ancestry from nine Scottish rural regions and the urban center of Edinburgh, as well as 96 unrelated individuals from the general U.K. population. Despite little overall differentiation on the basis of allele frequencies, there were clear differences among subpopulations in the extent of pairwise LD, measured between a subset of X-linked markers, that reflected presumed differences in the depths of the underlying genealogies within these subpopulations. Therefore, there are strategic advantages in studying rural subpopulations, in terms of increased power and reduced cost, that are lost by sampling across regions or within urban populations. Similar rural-urban contrasts are likely to exist in many other populations with stable rural subpopulations, which could influence the design of genetic association studies and national biobank data collections.

Genetics, Population↗
PubMed2005

KLOTHO genotype and cognitive ability in childhood and old age in the same individuals.

This study examined the influence of a variation in the KLOTHO gene on cognitive ability at age 11 and age 79 in 464 people from the Lothian Birth Cohort 1921 (LBC1921), and at age 11 and age 64 in 451 people in the Aberdeen Birth Cohort 1936 (ABC1936). In the LBC1921, people with the KLOTHO V/V genotype had lower verbal reasoning ability at age 11 and age 79, and lower non-verbal reasoning at age 79, than those with the F/F genotype, or heterozygotes. The effect of the KLOTHO polymorphism on cognition at age 79 was non-significant when adjusted for IQ at age 11. In this sample, KLOTHO V allele status accounts for about 2% of the variance in life-long traits related to verbal and non-verbal reasoning, but not to age-related cognitive change. These results were not replicated in the ABC1936 sample. In a combined analysis of the LBC1921 and the ABC1936 cohorts there was a significant KLOTHOxsex interaction: women with the V/V genotype had lower non-verbal reasoning scores at age 79, after adjustment for cognitive ability at age 11. Variation in the KLOTHO gene is a possible contributor to life-long reasoning differences in humans and/or to the ageing of non-verbal reasoning, especially in women.

Aged↗
PubMed2005

Nicastrin gene polymorphisms, cognitive ability level and cognitive ageing.

The hypothesis that polymorphisms in the gene for nicastrin (NCSTN) are associated with differences in cognitive level and ageing was tested in 462 relatively healthy surviving participants of the Scottish Mental Survey 1932. None had a history of dementia. They were tested on the Moray House Test of verbal reasoning at age 11 in 1932 and at age 79 between 1999 and 2001. At age 79 they also took tests of non-verbal reasoning, short- and long-term verbal declarative memory, Verbal Fluency, and a short screening test for dementia. Subjects who possessed at least one copy of the NCSTN B haplotype (Hap B) had higher scores on the Moray House Test (a test principally of verbal reasoning) at age 11 (p=0.036) and age 79 (p=0.027). The effect of Hap B on cognition at age 79 was non-significant after adjusting for the effect at age 11. Therefore, the effect of Hap B in this sample is on the life-long stable trait of cognitive ability, and not on age-related cognitive change. The possibility that this result might be a selection effect was not supported by the samples being in Hardy-Weinberg equilibrium with respect to the distribution of NCSTN genotypes.

Aged↗
PubMed2004

Apolipoprotein e gene variability and cognitive functions at age 79: a follow-up of the Scottish mental survey of 1932.

Apolipoprotein E (APOE) genotype is a possible influence on nonpathological cognitive aging. The authors studied 462 community-dwelling, 79-year-old people born in 1921, whose childhood IQ had been assessed in the Scottish Mental Survey of 1932 (Scottish Council for Research in Education, 1933). Adjusting for sex, childhood IQ, and self-reported illnesses, the authors found that those with an APOE e4 allele had significantly lower Wechsler Logical Memory (D. Wechsler, 1987) scores than those without an e4 allele. Those people with APOE s2/e3 genotypes had significantly higher Wechsler Logical Memory scores than e3/s3, who were significantly higher than e3/e4. Neither nonverbal reasoning nor verbal fluency were affected. In this sample, APOE genotype contributed to verbal memory in old age.

Aged↗
PubMed2004

Lost in transition--the Island of Susak (1951-2001).

The isolated population of the Island of Susak was thoroughly studied by a multidisciplinary team of the Croatian Academy of Sciences and Arts in early 1950's. Recently, a team of scientists revisited the island. This paper describes the main characteristics of the transition process during which a massive exodus occurred with 90% of the island's population migrating to New Jersey, USA. We summarise the differences in lifestyle, economy, social structure and sense of identity between the historic (1950's) and contemporary (2001) Susak population. We applied contemporary methods (analysis of microsatellite DNA polymorphisms) to investigate local myths about extreme levels of inbreeding and genetic homogeneity among the Susak islanders. Analysis of short-tandem-repeat (STR) loci showed that Susak displayed characteristics of a small homogeneous breeding isolate. The average heterozygosity was found to be low compared to outbred populations. The signature of a recent severe bottleneck could be detected. Analysis of 8 markers located on Xq13-21 in 71 individuals suggested extensive level of linkage disequilibrium (LD). A migrant study was designed to investigate the effects of large environmental changes (Susak vs. USA) and inbreeding (Susak vs. Croatian general population) on some biologically important quantitative traits, such as blood pressure and serum lipids. The results confirmed the positive correlation between inbreeding level and blood pressure that has been reported in the literature on several occasions. The last remnants of this traditional island community will soon be lost forever.

Anthropology↗