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Tim D Spector

Publications and source records attributed to Tim D Spector.

At least 19 recordsLinked to original sources
PubMed2026

Longitudinal dynamics of gene expression and metabolomics in an aging population cohort.

Multiomic profiling provides a comprehensive physiological overview at the molecular level, but understanding of its spatiotemporal dynamics remains limited in human populations. We profiled longitudinal whole-blood gene expression and metabolite levels in 335 females over 8 years. Levels of 5061 genes and 181 metabolites changed over time, with individual trajectories often diverging from population-level trends. Longitudinally variable genes showed cell type specificity and enrichment for aging-relevant pathways, including cardiometabolic and neurodegenerative disorders. Longitudinal trajectories were further shaped by genetics, circadian rhythm, seasonality, and environmental pollutant exposures. Integrative analyses revealed extensive static and time-variable cross-omic connectivity. Longitudinal profiling offers insight into the temporal evolution of age-related conditions at the molecular level, and understanding individual variation within these longitudinal patterns will be essential for future precision medicine approaches.

Female↗
PubMed2007

Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee.

OBJECTIVE: To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed-sex, case-control study of clinical knee OA. METHODS: Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50-86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately. RESULTS: The same FRZB 2-marker single-nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta-analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02). CONCLUSION: Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.

Aged↗
PubMed2007

Novel mutations in the small leucine-rich repeat protein/proteoglycan (SLRP) genes in high myopia.

The importance of the genetic component in high myopia has been well established in population and family studies, but only a few candidate genes have been explored to date. The extracellular matrix small leucine-rich repeat proteins/proteoglycans (SLRPs) regulate collagen fibril diameter and spacing. Given their role in extracellular matrix assembly and expression in the eye, they are likely to regulate its shape and size. Analysis of 85 English and 40 Finnish subjects with high myopia (refractive error of -6 diopters [D] or greater) resulted in 23 sequence variations in four SLRP genes, LUM, FMOD, PRELP, and OPTC. We observed higher number of variations in OPTC in English patients than in controls (p=0.042), and a possibly protective variation in LUM (c.893-105G>A) with p-value of 0.0043. Two intronic variations, six nonsynonymous and one synonymous amino acid changes, were not found in any of the nonmyopic controls. Five changes were detected in opticin, Thr177Arg, Arg229His, Arg325Trp, Gly329Ser, and Arg330His, and all but one (Arg229His) were shown to cosegregate with high myopia in families with incomplete penetrance. A homology model for opticin revealed that Arg229His and Arg325Trp are likely to disrupt the protein structure, and PolyPhen analysis suggested that Thr177Arg, Arg325Trp, and Gly329Ser changes may be damaging. A Leu199Pro change in lumican and Gly147Asp and Arg324Thr variations in fibromodulin are located in the highly conserved leucine-rich repeat (LRR) domains. This study provides new insight into the genetics of high myopia, suggesting that sequence variations in the SLRP genes expressed in the eye may be among the genetic risk factors underlying the pathogenesis of high myopia.

Amino Acid Sequence↗
PubMed2007

The SH2B gene is associated with serum leptin and body fat in normal female twins.

Src-homology-2 (SH2)-B, a Janus tyrosine kinase 2-interacting protein, has been identified recently as a key regulator of leptin and insulin sensitivity, glucose homeostasis, and body weight in mice. The aim of this study was to determine whether single-nucleotide polymorphisms (SNPs) in the human SH2B gene are associated with these variables. A tagging SNP (tSNP), Ala484Thr (rs7498665), was selected to represent five common SNPs (minor allele frequency > 0.05) in perfect linkage disequilibrium in a 16-kb region encompassing the SH2B gene. The tSNP was genotyped in 2455 white female twins (mean age, 47.4 +/- 12.6 years) from the St. Thomas' United Kingdom Adult Twin Registry (Twins United Kingdom). Ala484Thr (minor allele frequency, 0.38) was associated with serum leptin, total fat, waist circumference, and body weight (P = 0.02 to 0.04). The coding SNP has no predicted effect on protein structure or function and is likely to be in linkage disequilibrium with an as-yet unidentified functional variant in the SH2B gene. Our results support a role for SH2-B in modulating the regulation of body weight and fat by leptin in this female population. If SH2-B signaling is attenuated in diet-induced obesity, it could become a target for drug-induced leptin sensitization.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Genetic influences on exercise participation in 37,051 twin pairs from seven countries.

BACKGROUND: A sedentary lifestyle remains a major threat to health in contemporary societies. To get more insight in the relative contribution of genetic and environmental influences on individual differences in exercise participation, twin samples from seven countries participating in the GenomEUtwin project were used. METHODOLOGY: Self-reported data on leisure time exercise behavior from Australia, Denmark, Finland, Norway, The Netherlands, Sweden and United Kingdom were used to create a comparable index of exercise participation in each country (60 minutes weekly at a minimum intensity of four metabolic equivalents). PRINCIPAL FINDINGS: Modest geographical variation in exercise participation was revealed in 85,198 subjects, aged 19-40 years. Modeling of monozygotic and dizygotic twin resemblance showed that genetic effects play an important role in explaining individual differences in exercise participation in each country. Shared environmental effects played no role except for Norwegian males. Heritability of exercise participation in males and females was similar and ranged from 48% to 71% (excluding Norwegian males). CONCLUSIONS: Genetic variation is important in individual exercise behavior and may involve genes influencing the acute mood effects of exercise, high exercise ability, high weight loss ability, and personality. This collaborative study suggests that attempts to find genes influencing exercise participation can pool exercise data across multiple countries and different instruments.

Adult↗
PubMed2006

Genomewide linkage scan of hand osteoarthritis in female twin pairs showing replication of quantitative trait loci on chromosomes 2 and 19.

BACKGROUND AND OBJECTIVE: Until recently, there has been little agreement between conflicting results of osteoarthritis (OA) linkage. The purpose of this study was to conduct a whole-genome linkage scan to identify susceptibility loci for idiopathic hand OA in a large, population-based sample of females. METHODS: Two OA-related radiographic phenotypes DIP (distal interphalangeal joints)-OA and Tot-KL (Kellgren-Lawrence score for both hands) chosen a priori were examined on 538 (269 pairs) monozygous and 1256 (628 pairs) dizygous (DZ) females. A genome-wide scan using microsatellite markers spaced 10 cM apart was performed on 1028 DZ twins. First, the heritability of the two OA phenotypes was estimated. Next, multipoint linkage analysis was conducted using a modified version of the Haseman-Elston method in a generalised linear model. RESULTS: Heritability for DIP-OA and Tot-KL was found to be 47.6% and 67.4%, respectively. A genome-wide scan produced reliable evidence of significant linkage of DIP-OA on chromosome 2 at 90 cM (logarithmic odds ratio (LOD) = 2.90) and for Tot-KL on chromosome 19 at 65 cM (LOD = 4.26). These results are in agreement with data published previously. Several other significant linkage peaks were observed-for example, on chromosome 1 at 250 cM and on chromosome 3 at 30 cM-but were confirmed less reliably. CONCLUSION: This is one of the largest OA linkage studies performed to date and provides clear evidence for linkage at two quantitative trait loci (on chromosome 2 at 90 cM and on chromosome 19 at 65 cM). As the results were robust and replicated in previous smaller studies, the fine mapping of these regions is a logical next step to pinpoint potential susceptibility gene(s) of interest.

Chromosome Aberrations↗
PubMed2006

Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration.

BACKGROUND: Rheumatoid arthritis (RA) is associated with reduced lifespan and shortened telomere length in lymphocytes, but the mechanism underlying this is unclear. Telomere loss in white blood cells (WBC) is accelerated by oxidative stress and inflammation in vitro. It was postulated that the accelerated WBC telomere shortening in RA occurs as a result of exposure to chronic inflammation. OBJECTIVES: To measure telomere terminal restriction fragment (TRF) length in a large cohort of RA cases and healthy controls, to explore associations of TRF length with features of disease and with RA-associated HLA-DRB1 alleles. METHODS: WBC and TRF length were measured by Southern blot in DNA from 176 hospital-based RA cases satisfying the 1987 American College of Rheumatology criteria and from 1151 controls. TRF length was compared between cases and controls, and the effects of disease duration, severity and HLA-DRB1 alleles encoding the shared epitope (SE) were assessed. RESULTS: Age- and sex-adjusted TRF length was significantly shorter in RA cases compared with controls (p<0.001). There was no association between age- and sex-adjusted TRF length and disease duration, C reactive protein or Larsen score. The presence of one or more SE-encoding alleles was associated with reduced adjusted TRF length in RA cases (SE positive vs SE negative cases, p=0.038), but not in controls. CONCLUSION: The reduced TRF length in a large group of patients with RA compared with controls has been shown. The reduction is apparently independent of disease duration and markers of disease severity, but is influenced by HLA-DRB1 genotype.

Age Factors↗
PubMed2006

Human telomere biology: pitfalls of moving from the laboratory to epidemiology.

Remarkable progress has been made during the last 2 decades in understanding telomere biology at the molecular and cellular levels. Clinical epidemiology research of human telomeres, in contrast, is a discipline just coming into its own. The most important observation in studying human telomere biology is that telomere length is highly variable among humans. Here we explain some of the reasons for this variability and propose several principles that should be considered in conducting epidemiological telomere research. Ignoring these principles could lead to misleading conclusions.

Aged↗
PubMed2006

Genome-wide search for nevus density shows linkage to two melanoma loci on chromosome 9 and identifies a new QTL on 5q31 in an adult twin cohort.

The density of acquired melanocytic nevi represents an important risk factor for malignant melanoma. Total body nevus counts were collected in a cross-sectional study of 1730 healthy females from the UK Adult twin registry comprising 709 dizygous and 156 monozygous pairs. Nevus density (ND) increased up to the age of 35 years and then gradually declined. Quantitative genetic analysis showed a smaller genetic influence (36%) on ND up to 35 years, compared with after 35 years where it rose to 59%. Using a sub-sample of 1238 genotyped individuals, we performed distinct genome-wide scans for individuals above and below 35 separately. In the younger sub-sample, we confirmed a quantitative trait locus (QTL) for ND on chromosomes 9p21 (LOD=2.54), a region already linked to both familial melanoma and ND. We also observed a linkage signal on 9q21 (LOD=2.55) overlapping a recently reported susceptibility locus for ocular and cutaneous melanoma in Danish families. The strongest evidence of linkage identified a novel QTL on chromosome 5q31-32 (LOD=3.47). None of these linkages was observed in the group aged 35 years and over, which showed suggestive linkage on chromosome 2p24 (LOD=2.75). To the best of our knowledge, this is the first genome-wide search for ND in a large sample of healthy adults. The results suggest that different sets of genes are likely to influence the processes leading to the appearance of nevi and their involution. They provide both novel and replicated QTLs for nevus development, some of which might overlap with those for melanoma and warrant detailed investigation.

Adult↗
PubMed2006

cMYB is involved in the regulation of fetal hemoglobin production in adults.

A quantitative trait locus (QTL) controlling HbF levels has previously been mapped to chromosome 6q23 in an Asian-Indian kindred with beta thalassemia and heterocellular hereditary persistence of fetal hemoglobin (HPFH). Five protein-coding genes, ALDH8A1, HBS1L, cMYB, AHI1, and PDE7B reside in this 1.5-megabase (Mb) candidate interval of 6q23. To direct sequencing efforts we compared the expression profiles of these 5 genes between 12 individuals with elevated and 14 individuals with normal HbF levels during adult erythropoiesis by real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR). Two genes, cMYB and HBS1L, demonstrated simultaneous transcriptional down-regulation in individuals with elevated HbF levels. Transfection of K562 cells encoding human cDNA of cMYB and HBS1L genes showed that, although overexpression of ectopic cMYB inhibited gamma-globin gene expression, overexpression of HBS1L had no effect. Low levels of cMYB were associated with low cell expansions, accelerated erythroid maturation, and higher number of macrophages in erythroid cell culture. These observations suggest that differences in the intrinsic levels of cMYB may account for some of the variation in adult HbF levels. The possible mechanism of cMYB influencing gamma- to beta-globin switching is discussed.

Adult↗
PubMed2006

Twins: A cloning experience.

Drawing upon qualitative interviews with monozygotic (identical) twins sharing 100% of their genes, and with dizygotic (fraternal) twins and singletons as control groups, this paper explores what it means to be genetically identical. (The twins interviewed were from the TwinsUK register in London.) In the context of the ongoing debate on human reproductive cloning, it examines questions such as: To what extent do identical twins perceive their emotional and physical bond to be a result of their genetic makeup? What would they think if they had been deliberately created genetically identical? How would they feel about being genetically identical to a person who was born a few years earlier or later? First, our respondents ascribed no great significance to the role of genes in their understanding of what it means to be identical twins. Second, the opinion that human reproductive cloning would "interfere with nature", or "contradict God's will", was expressed by our respondents exclusively on the abstract level. The more our respondents were able to relate a particular invented cloning scenario to their own life-worlds, the lower the prevalence of the argument. Third, for all three groups of respondents, the scenario of having been born in one of the other groups was perceived as strange. Fourth, the aspect that our respondents disliked about cloning scenarios was the potential motives of the cloners. Without equating monozygotic twins directly with "clones", these results from "naturally" genetically identical individuals add a new dimension to what a future cloning situation could entail: The cloned person might possibly (a) perceive a close physical and emotional connection to the progenitor as a blessing; (b) suffer from preconceptions of people who regard physical likeness as a sign of incomplete individuality; and (c) perceive the idea of not having been born a clone of a particular person as unpleasant.

Cloning, Organism↗
PubMed2006

Intrauterine, environmental, and genetic influences in the relationship between birth weight and lipids in a female twin cohort.

OBJECTIVE: To investigate the association between birth weight and lipid levels in a cohort of UK female twins. METHODS AND RESULTS: Birth weights and fasting blood lipid levels were available for 2900 women aged 18 to 80 years. Individual level regressions indicated that a 1-kg increase in birth weight was associated with a 0.08-mmol/L decrease in total cholesterol (95% confidence interval [CI], -0.12, -0.04) and a 0.06-mmol/L decrease in low-density lipoprotein (-0.10, -0.03). Using a regression model that includes both mean twin pair birth weight and individual twin's difference from the pair mean, we found that these significant relationships were between twin pairs only and not within pairs. We found no significant relationships for high-density lipoprotein. When monozygotic and dizygotic twins were analyzed separately we found similar effect sizes. Restricting the analysis to postmenopausal women we found stronger relationships between birth weight and lipid levels, which was attenuated after adjustment for body mass index (BMI). CONCLUSIONS: These novel results suggest that significant relationships between birth weight and lipids are mediated through shared influences on the maternal environment and do not support the hypothesis that fetal malnutrition is an important determinant of adult lipid levels. Adjustment for BMI also indicates that postnatal growth may be more important than prenatal growth.

Adult↗
PubMed2006

Joint linkage and association of six single-nucleotide polymorphisms in the factor XIII-A subunit gene point to V34L as the main functional locus.

OBJECTIVE: Activated factor XIII (FXIII) crosslinks fibrin to enhance the mechanical strength of a blood clot and increase its resistance to fibrinolysis. The prevalence of a common variant in the FXIII-A gene (V34L) has been reported to be lower in patients with myocardial infarction and ischemic stroke than in controls, suggesting a protective role for this polymorphism in vascular diseases. The current study investigated 6 single-nucleotide polymorphisms (SNPs) within the FXIII A-subunit gene to locate functional polymorphism(s) responsible for variation in FXIII activation. METHODS AND RESULTS: A total of 201 dizygotic twin pairs were genotyped for 1 promoter and all common nonsynonymous coding polymorphisms in the FXIII A-subunit gene: -246G>A, V34L, Y204F, P564L, V650I, and E651Q. Tests of linkage, association, and combined linkage and association were performed using QTDT software. Significant linkage to the V34L polymorphism (P=5 x 10(-12)) as well as association (P=3 x 10(-49)) was observed. Adjusting for association while performing linkage made the linkage signal disappear for the V34L polymorphism (from chi2=47.55, P=5x10(-12) to chi2=1.30, P=0.25). Only haplotypes containing the 34L allele showed association with FXIII activation. CONCLUSIONS: Testing multiple SNPs in the FXIII A-subunit gene indicates that V34L is the main functional polymorphism influencing FXIII activation.

Adult↗
PubMed2006

Mapping genetic loci that determine leukocyte telomere length in a large sample of unselected female sibling pairs.

Telomeres play a central role in cellular senescence and cancer pathobiology and are associated with age-related diseases such as atherosclerosis and dementia. Telomere length varies between individuals of the same age, is influenced by DNA-damaging factors such as oxidative stress, and is heritable. We performed a quantitative-trait linkage analysis using an approximate 10-cM genomewide map for mean leukocyte terminal-restriction fragment (TRF) lengths measured by Southern blotting, in 2,050 unselected women aged 18-80 years, comprising 1,025 complete dizygotic twin pairs. Heritability of mean batch-adjusted TRF was 36% (95% confidence interval [CI] 18%-48%), with a large common environmental effect of 49% (95% CI 40%-58%). Significant linkage was observed on chromosome 14 (LOD 3.9) at 14q23.2, and suggestive linkage at 10q26.13 (LOD 2.4) and 3p26.1 (LOD 2.7). This is the first report of loci, mapped in a sample of healthy individuals, that influence mean telomere variation in humans.

Chromosome Mapping↗
PubMed2006

Reproducible genetic associations between candidate genes and clinical knee osteoarthritis in men and women.

OBJECTIVE: Osteoarthritis (OA) is recognized to have a genetic component, and in this study, we aimed to replicate in a case-control study of men and women with clinical knee OA genetic associations in 12 candidate genes previously reported to be associated with OA. METHODS: Twenty-five single-nucleotide polymorphisms were genotyped in 298 men and 305 women ages 50-86 who were diagnosed as having knee OA, as assessed both clinically and radiographically, and in 297 men and 299 women matched for age and ethnicity (controls). Standardized anteroposterior radiographs of the knee in extension were performed on each of the cases, and all cases met the American College of Rheumatology criteria for OA of the knee. Genotype and haplotype frequencies in cases and controls were compared separately in men and women. The 12 genes tested were AACT, ADAM12, BMP2, CD36, CILP, COX2, ESR1, NCOR2, OPG, TNA, TNFAIP6, and VDR. RESULTS: Eight of the candidate genes were associated in women and 5 in men, and only 3 genes (TNFAIP6, NCOR2, and CD36) were not significantly associated in either sex. The strongest associations in terms of odds ratios (ORs) were a haplotype in ADAM12 (OR 7.1 [95% confidence interval (95% CI) 3.3-33.8]) and a haplotype in ESR1 (OR 3.6 [95% CI 1.18-10.98]) in women. The same ADAM12 haplotype (OR 2.54 [95% CI 1.2-5.4]) and a haplotype in the CILP gene (OR 0.38 [95% CI 0.23-0.62]) were the strongest associations in men. CONCLUSION: We found that genes previously identified by their association with subclinical features of knee OA or progression were also associated with clinical knee OA. These genetic associations may identify individuals at a particularly high risk of developing knee OA.

Aged↗
PubMed2006

Association between a variation in LRCH1 and knee osteoarthritis: a genome-wide single-nucleotide polymorphism association study using DNA pooling.

OBJECTIVE: To perform a large-scale association analysis of single-nucleotide polymorphisms (SNPs) in patients with radiographically defined osteoarthritis (OA) of the knee. METHODS: We examined >25,000 SNPs located within approximately 14,000 genes for associations with radiographically defined knee OA, using polymerase chain reaction and MassExtend amplification techniques. Allele frequencies were estimated initially in DNA pools from 335 female patients with knee OA and 335 asymptomatic and radiographically negative female control subjects. All were of northern European ancestry. Significant allele frequency differences were validated by genotyping of individual DNA samples. Confirmed significant findings were verified in 2 additional case-control samples from the UK (443 cases and 303 controls) and Newfoundland (346 cases and 264 controls). Chondrosarcoma cell lines were used to test for potential differences in gene expression. RESULTS: The marker most strongly associated with the risk of knee OA was rs912428, a C/T polymorphism in intron 1 of LRCH1, a gene on chromosome 13q14 that encodes a novel protein of as-yet-unknown function. The frequency of the T allele compared with controls was consistently increased by 40% across all 3 case-control groups. Additional subanalyses in case-control samples with hip OA and hand OA suggested similar trends, but did not reach statistical significance. Association fine-mapping using 10 additional SNPs in LRCH1 confirmed intron 1 as the region of highest association but failed to reveal variations with significance stronger than the marker SNP, as did the haplotype analysis. LRCH1 was not up-regulated or overexpressed in chondrosarcoma cell lines exposed to inflammatory stimuli, suggesting a possible structural role. CONCLUSION: A genetic variant in LRCH1 was consistently associated with knee OA in 3 samples from 2 populations. Our results also suggest that the same association with OA may exist at other sites. Additional genetic and experimental work is needed to elucidate the precise mechanism by which the LRCH1 gene influences OA risk.

Aged↗
PubMed2006

The heritable determinants of cartilage oligomeric matrix protein.

OBJECTIVE: Cartilage oligomeric matrix protein (COMP) is a cartilage matrix macromolecule. The protein is detectable in serum and has been investigated as a biomarker of osteoarthritis (OA). An association between COMP and OA has been shown, yet the precise factors governing serum levels of COMP remain unclear. The aim of this study was to determine whether genetic factors influence serum levels of COMP. METHODS: A classic twin study was conducted using COMP levels in serum obtained from healthy female twin volunteers. COMP levels were determined by an inhibition enzyme-linked immunosorbent assay method. The heritability of COMP was determined by comparing correlation among 160 monozygotic and 349 dizygotic twin pairs. Data on potential confounding factors, including age, body mass index, and the presence of OA as assessed by hand, hip, and knee radiographs, were included in the analysis. RESULTS: Serum levels of COMP showed a correlation of 0.72 (95% confidence interval [95% CI] 0.65-0.80) among monozygotic twin pairs and 0.47 (95% CI 0.39-0.55) in dizygotic pairs. This equated to an estimated heritability for COMP of 40% (95% CI 20-60%). Although age and body mass index were found to be significantly associated with COMP in regression analysis, taking the effects of these factors into account did not influence the estimate of heritability. CONCLUSION: This study showed that heritable factors influence serum levels of the cartilage matrix biomarker COMP. Together with other published data, the results suggest that genetic factors operate at an early stage in the etiologic pathways that influence the development of radiographically discernible OA.

Adult↗