Antioxidant supplements may reduce age-related macular degeneration (AMD) progression. The macular carotenoids are of particular interest because of their biochemical, optical, and anatomic properties. This classic twin study was designed to determine the heritability of macular pigment (MP) augmentation in response to supplemental lutein (L) and zeaxanthin (Z).
A total of 322 healthy female twin volunteers, aged 16–50 years (mean 40 ± 8.7) was enrolled in a prospective, nonrandomized supplement study. Macular pigment optical density (MPOD) measurements using two techniques (2-wavelength fundus autofluorescence [AF] and heterochromatic flicker photometry [HFP]), and serum concentrations of L and Z, were recorded at baseline, and at 3 and 6 months following daily supplementation with 18 mg L and 2.4 mg Z for a study period of 6 months.
At baseline, mean MPOD was 0.44 density units (SD 0.21, range 0.04–1.25) using HFP, and 0.41 density units (SD 0.15) using AF. Serum L and Z levels were raised significantly from baseline following 3 months' supplementation (mean increase 223% and 633%, respectively, P < 0.0001 for both), with no MPOD increase. After 6 months' supplementation, a small increase in MPOD was seen (mean increase 0.025 ± 0.16, P = 0.02, using HFP). Subdivision of baseline MPOD into quartiles revealed that baseline levels made no difference to the treatment effect. Genetic factors explained 27% (95% confidence interval [CI] 7–45) of the variation in MPOD response. Distribution profiles of macular pigment did not change in response to supplementation.
MPOD response to supplemental L and Z for a period of 6 months was small (an increase over baseline of 5.7% and 3.7%, measured using HFP and AF, respectively), and was moderately heritable. Further study is indicated to investigate the functional and clinical impact of supplementation with the macular carotenoids.
A classical twin study of 322 twins determined the heritability of macular pigment augmentation in response to 6 months' supplemental lutein and zeaxanthin. There was a small increase in macular pigment optical density, which was moderately heritable; genetic factors explained 27% of variance.
Fibrin makes up the structural basis of an occlusive arterial thrombus and variability in fibrin phenotype relates to cardiovascular risk. The aims of the current study from the EU consortium EuroCLOT were to 1) determine the heritability of fibrin phenotypes and 2) identify QTLs associated with fibrin phenotypes.
447 dizygotic (DZ) and 460 monozygotic (MZ) pairs of healthy UK Caucasian female twins and 199 DZ twin pairs from Denmark were studied. D-dimer, an indicator of fibrin turnover, was measured by ELISA and measures of clot formation, morphology and lysis were determined by turbidimetric assays. Heritability estimates and genome-wide linkage analysis were performed.
Estimates of heritability for d-dimer and turbidometric variables were in the range 17 - 46%, with highest levels for maximal absorbance which provides an estimate of clot density. Genome-wide linkage analysis revealed 6 significant regions with LOD>3 on 5 chromosomes (5, 6, 9, 16 and 17).
The results indicate a significant genetic contribution to variability in fibrin phenotypes and highlight regions in the human genome which warrant further investigation in relation to ischaemic cardiovascular disorders and their therapy.
linkage; quantitative trait loci; twin; cardiovascular disease; thrombosis
To examine the relative roles of genetic and environmental factors in central retinal thickness, by performing a classical twin study.
310 subjects were recruited from the TwinsUK adult registry at St Thomas' Hospital. Optical coherence tomography (Zeiss, stratus OCT3) was used to measure the average retinal thickness in the central 1 mm diameter area. The covariance of central retinal thickness (CRT), within MZ and DZ twin pairs, was compared and genetic modelling techniques were used to determine the relative contributions of genes and environment to the variation in CRT observed in this population.
Main outcome measure
CRT (average retinal thickness in the central 1 mm diameter area, centred on the fovea).
The mean CRT of all subjects was 212.1 μm (range 165–277). CRT was statistically related to refractive error, with increasing myopia associated with a thinner CRT. CRT was more highly correlated within MZ twin pairs (r = 0.88) than with DZ twin pairs (r = 0.58), suggesting a genetic role. A model combining additive genetic and unique environmental factors provided the best fitting model and gave a heritability estimate of 0.90.
Genetic factors appear to play an important role in CRT, with a heritability estimate of 0.90.
Recent studies have identified both heritable DNA methylation effects and differential methylation in disease-discordant identical twins. Larger sample sizes, replication, genetic-epigenetic analyses and longitudinal assays are now needed to establish the role of epigenetic variants in disease.
Epigenetics; DNA methylation; twins; heritability; epigenome-wide association studies; EWAS
Using whole blood from 15 twin pairs discordant for breast cancer and high-resolution (450K) DNA methylation analysis, we identified 403 differentially methylated CpG sites including known and novel potential breast cancer genes. Confirming the results in an independent validation cohort of 21 twin pairs determined the docking protein DOK7 as a candidate for blood-based cancer diagnosis. DNA hypermethylation of the promoter region was also seen in primary breast cancer tissues and cancer cell lines. Hypermethylation of DOK7 occurs years before tumor diagnosis, suggesting a role as a powerful epigenetic blood-based biomarker as well as providing insights into breast cancer pathogenesis.
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.
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.
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.
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.
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.
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.
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.
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.
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-related hearing impairment (ARHI) affects 25–40% of individuals over the age of 65. Despite the high prevalence of this complex trait, ARHI is still poorly understood. We hypothesized that variance in hearing ability with age is largely determined by genetic factors. We collected audiologic data on females of Northern European ancestry and compared different audiogram representations. A web-based speech-to-noise ratio (SNR) hearing test was compared with pure-tone thresholds to see if we could determine accurately hearing ability on people at home and the genetic contribution to each trait compared. Volunteers were recruited from the TwinsUK cohort. Hearing ability was determined using pure-tone audiometry and a web-based hearing test. Different audiogram presentations were compared for age-correlation and reflection of audiogram shape. Using structural equation modelling based on the classical twin model the heritability of ARHI, as measured by the different phenotypes, was estimated and shared variance between the web-based SNR test and pure-tone audiometry determined using bivariate modelling. Pure-tone audiometric data was collected on 1033 older females (age: 41–86). 1970 volunteers (males and females, age: 18–85) participated in the SNR. In the comparison between different ARHI phenotypes the difference between the first two principle components (PC1–PC2) best represented ARHI. The SNR test showed a sensitivity and specificity of 89% and 80%, respectively, in comparison with pure-tone audiogram data. Univariate heritability estimates ranged from 0.70 (95% CI: 0.63–0.76) for (PC1–PC2) to 0.56 (95% CI: 0.48–0.63) for PC2. The genetic correlation of PC1–PC2 and SNR was −0.67 showing that the 2 traits share variances attributed to additive genetic factors. Hearing ability showed considerable heritability in our sample. We have shown that the SNR test provides a useful surrogate marker of hearing. This will enable a much larger sample to be collected at a fraction of the cost, facilitating future genetic association studies.
Female sexual dysfunction (FSD) is an important but controversial problem with serious negative impact on women’s quality of life. Data from twin studies have shown a genetic contribution to the development and maintenance of FSD.
We performed a genome-wide association study (GWAS) on 2.5 million single-nucleotide polymorphisms (SNPs) in 1,104 female twins (25–81 years of age) in a population-based register and phenotypic data on lifelong sexual functioning. Although none reached conventional genome-wide level of significance (10×-8), we found strongly suggestive associations with the phenotypic dimension of arousal (rs13202860, P = 1.2×10−7; rs1876525, P = 1.2×10−7; and rs13209281 P = 8.3×10−7) on chromosome 6, around 500kb upstream of the locus HTR1E (5-hydroxytryptamine receptor 1E) locus, related to the serotonin brain pathways. We could not replicate previously reported candidate SNPs associated with FSD in the DRD4, 5HT2A and IL-1B loci.
We report the first GWAS of FSD symptoms in humans. This has pointed to several “risk alleles” and the implication of the serotonin and GABA pathways. Ultimately, understanding key mechanisms via this research may lead to new FSD treatments and inform clinical practice and developments in psychiatric nosology.
There is a great need for identification of biomarkers that could improve the prediction of early osteoarthritis (OA). We undertook this study to determine whether circulating levels of interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and C-reactive protein (CRP) can serve as useful markers of radiographic knee OA (RKOA) in a normal human population.
RKOA data were obtained from the cohort of the Chingford Study, a prospective population-based study of healthy, middle-aged British women. The RKOA-affected status of the subjects was assessed using the Kellgren/Lawrence (K/L) grade as determined on radiographs obtained at baseline (n = 908) and at 10 years and 15 years thereafter. Serum levels of CRP, IL-6, and TNFα were assayed at 5, 8, and 15 years, using high-sensitivity commercial assays. A K/L grade of ≥2 in either knee was used as the outcome measure. Statistical analyses included analysis of variance for repeated measurements and logistic regression models, together with longitudinal modeling of dichotomous responses.
During 15 years of followup, the prevalence of RKOA (K/L grade ≥2) increased from 14.7% to 48.7% (P < 0.00001 versus baseline). The body mass index (BMI) and circulating levels of CRP and IL-6 were consistently and significantly higher in subjects diagnosed as having RKOA. When multiple logistic regression was applied to the data, the variables of older age (P = 3.93 × 10−5), higher BMI at baseline (P = 0.0003), and increased levels of IL-6 at year 5 (P = 0.0129) were determined to be independent predictors of the appearance of RKOA at year 10. The results were fully confirmed using longitudinal modeling of repeated measurements of the data obtained at 3 visits. The odds ratio for RKOA in subjects whose IL-6 levels were in the fourth quartile of increasing levels (versus the first quartile) was 2.74 (95% confidence interval 1.94–3.87).
This followup study showed that individuals were more likely to be diagnosed as having RKOA if they had a higher BMI and increased circulating levels of IL-6. These results should stimulate more work on IL-6 as a potential therapeutic target.
The mitochondrial theory of ageing proposes that damage to mitochondria and diminished mitochondrial DNA (mtDNA) repair are major contributors to cellular dysfunction and age-related diseases. We investigate the prevalence of heteroplasmy in the mtDNA control region in buccal swab and blood derived samples for 178 women from the TwinsUK cohort (41 DZ pair 39 MZ pairs, 18 singletons, mean age 57.5 range 28–82) and its relationship to age, BMI and fasting insulin and glucose serum levels. The overall estimated prevalence of heteroplasmy for both tissues in the control region measured for 37 sites was 17%. The prevalence of heteroplasmy was higher among the older half of the study subjects than in the younger half (23% vs 10% p<0.03), primarily reflecting the increase in the prevalence of a heteroplasmic dinucleotide CA repeat in variable region II (VRII) with age. The VRII 523–524 heteroplasmic site (heteroplasmic in 25 subjects) was also associated with a decrease in BMI. In addition, concordance rates for common heteroplasmy were observed to be near complete for both dizygotic (DZ = 94%) and monozygotic twin pairs (MZ = 100%), consistent with previous reports that suggest variation in heteroplasmy rates between generations are determined by bottlenecks in maternal transmission of mitochondria. Differences in the prevalence of heteroplasmy were observed overall between samples derived from buccal swabs (19%) and blood (15%, p<0.04). These were particularly marked at position 16093 of hypervariable region I (HVI, 7% vs 0%, respectively, p<4×10−11). The presence of the C allele at position 16093 in blood was associated with the presence of heteroplasmy in buccal swabs at this position (p = 3.5×10−14) and also at VRII (p = 2×10−4) suggesting a possible predisposing role for this site in the accumulation of heteroplasmy. Our data indicate that BMI is potentially associated with control region heteroplasmy.
Retinal arteriolar and venular calibers have a high phenotypic correlation caused by a shared genetic correlation. Identifying vessel pleiotropic genes will elucidate the nature of vessel association with specific cardiovascular disease risk factors.
Retinal arteriolar and venular calibers are highly heritable and associated with cardiovascular disease. This study was designed to investigate the relative influence of genetic and environmental factors on the high phenotypic correlation (r = 0.59) between these two traits and to assess the shared and specific influence of established and novel cardiovascular disease risk factors on them.
A total of 1463 Caucasian female twins (706 monozygotic and 757 dizygotic), between 24 and 79 years of age, underwent retinal photography from which retinal arteriolar (mean, 153.75 ± 22.1 μm, SD) and venular (mean, 232.1 ± 36.6 μm) calibers were measured with semiautomated software. A bivariate heritability model was used to assess the genetic and environmental influences underlying both specific trait variance and the covariance between the vessel traits. The investigation was an assessment of phenotypic associations between retinal arteriolar and venular calibers and cardiovascular disease risk factors.
Additive genetic factors accounted for approximately three fourths of the covariance between retinal arteriolar and venular calibers within the cohort. This finding was replicated in a sample of 1981 twins from the Australian Twins Eye Study. The partial correlation showed that known risk factors accounted for only 5% of the covariance between arteriolar and venular calibers. Novel associations were found between venular caliber and β-cell function (P = 0.011) and insulin sensitivity (P = 0.002).
These results suggest that future gene-mapping studies may identify pleiotropic genetic variants influencing both retinal arteriolar and venular calibers. Genetic variants associated with retinal caliber and (risk factors for) cardiovascular disease should provide new etiologic insights into this complex disease.
Our aim was to examine the association between serum dehydroepiandrosterone sulfate (DHEAS) at baseline and BMD change at the femoral neck (FN) and lumbar spine (LS) in postmenopausal women during a 15-year follow-up. All participants were from the Chingford Study. BMD at the FN and LS were measured eight times during the 15-year follow-up by dual-energy X-ray absorptiometry. DHEAS at baseline was measured using radioimmunoassay. Data on height, weight, and hormone-replacement therapy (HRT) status were obtained at each visit. Multilevel linear regression modeling was used to examine the association between longitudinal BMD change at the FN and LS and DHEAS at baseline. Postmenopausal women (n = 1,003) aged 45–68 years (mean 54.7) at baseline were included in the study. After adjustment for baseline age, estradiol, HRT, and BMI, BMD at the FN decreased on average 0.49% (95% CI 0.31–0.71%) per year; and the decline was slowed down by 0.028% per squared year. Increase of DHEAS (each micromole per liter) was associated with 0.49% less bone loss at the FN (95% CI 0.21–0.71%, P = 0.001). However, this strong association became slightly weaker over time. Similar but weaker results were obtained for LS BMD. Our data suggest that high serum DHEAS at baseline is associated with less bone loss at both FN and LS and this association diminishes over time. The nature of the association is unclear, but such an association implies that, in managing BMD loss, women might benefit from maintaining a high level of DHEAS.
BMD; DHEAS; Osteoporosis; Longitudinal study; Postmenopausal
The number and volume of cells in the blood affect a wide range of disorders including cancer and cardiovascular, metabolic, infectious and immune conditions. We consider here the genetic variation in eight clinically relevant hematological parameters, including hemoglobin levels, red and white blood cell counts and platelet counts and volume. We describe common variants within 22 genetic loci reproducibly associated with these hematological parameters in 13,943 samples from six European population-based studies, including 6 associated with red blood cell parameters, 15 associated with platelet parameters and 1 associated with total white blood cell count. We further identified a long-range haplotype at 12q24 associated with coronary artery disease in 9,479 cases and 10,527 controls. We show that this haplotype demonstrates extensive disease pleiotropy, as it contains known risk loci for type 1 diabetes, hypertension and celiac disease and has been spread by a selective sweep specific to European and geographically nearby populations.
Lumbar disc degeneration (LDD) is prevalent, age-related and contributes to low back pain. Cross-sectional LDD as determined by MRI scan is known to be highly heritable. The authors postulated that the rate of progression might also be controlled by genetic factors.
A 10-year follow-up of MRI-determined LDD was performed in 234 pairs of twin volunteers in the UK and Australia, comprising 90 monozygotic pairs and 144 dizygotic same-sex twin pairs. Of the total sample, 95% were female. The mean age at baseline was 53.3 years (range 32.3–69.5). The rate of progression was calculated and, because the effect of age was non-linear, the sample was divided into age strata and heritability estimated for each trait's progression.
All MRI-determined traits worsened significantly over the period of follow-up (p<0.0001 for each). Change in disc height was not heritable at any age while posterior disc bulge was heritable across all age categories (range 28–53%), with higher heritability in those over 60 years. Change in disc signal intensity and anterior osteophytes were found to be heritable only in those aged under 50 years at baseline (heritability estimates 76% (95% CI 44% to 100%) and 74% (42% to 100%), respectively).
Longitudinal change in LDD traits is heritable for all traits except disc height, but there is a significant influence of age, which varies across traits. Future studies to define the genetic variants influencing LDD progression should examine MRI traits individually and in women should focus on those under 50 years of age.
The regulation of gene expression plays a pivotal role in complex phenotypes, and epigenetic mechanisms such as DNA methylation are essential to this process. The availability of next-generation sequencing technologies allows us to study epigenetic variation at an unprecedented level of resolution. Even so, our understanding of the underlying sources of epigenetic variability remains limited. Twin studies have played an essential role in estimating phenotypic heritability, and these now offer an opportunity to study epigenetic variation as a dynamic quantitative trait. High monozygotic twin discordance rates for common diseases suggest that unexplained environmental or epigenetic factors could be involved. Recent genome-wide epigenetic studies in disease-discordant monozygotic twins emphasize the power of this design to successfully identify epigenetic changes associated with complex traits. We describe how large-scale epigenetic studies of twins can improve our understanding of how genetic, environmental and stochastic factors impact upon epigenetics, and how such studies can provide a comprehensive understanding of how epigenetic variation affects complex traits.
Patterns of food intake and prevalent osteoarthritis of the hand, hip, and knee were studied using the twin design to limit the effect of confounding factors. Compounds found in associated food groups were further studied in vitro.
Cross-sectional study conducted in a large population-based volunteer cohort of twins. Food intake was evaluated using the Food Frequency Questionnaire; OA was determined using plain radiographs. Analyses were adjusted for age, BMI and physical activity. Subsequent in vitro studies examined the effects of allium-derived compounds on the expression of matrix-degrading proteases in SW1353 chondrosarcoma cells.
Data were available, depending on phenotype, for 654-1082 of 1086 female twins (median age 58.9 years; range 46-77). Trends in dietary analysis revealed a specific pattern of dietary intake, that high in fruit and vegetables, showed an inverse association with hip OA (p = 0.022). Consumption of 'non-citrus fruit' (p = 0.015) and 'alliums' (p = 0.029) had the strongest protective effect. Alliums contain diallyl disulphide which was shown to abrogate cytokine-induced matrix metalloproteinase expression.
Studies of diet are notorious for their confounding by lifestyle effects. While taking account of BMI, the data show an independent effect of a diet high in fruit and vegetables, suggesting it to be protective against radiographic hip OA. Furthermore, diallyl disulphide, a compound found in garlic and other alliums, represses the expression of matrix-degrading proteases in chondrocyte-like cells, providing a potential mechanism of action.
Psychiatric disorders such as schizophrenia are commonly accompanied by cognitive impairments that are treatment resistant and crucial to functional outcome. There has been great interest in studying cognitive measures as endophenotypes for psychiatric disorders, with the hope that their genetic basis will be clearer. To investigate this, we performed a genome-wide association study involving 11 cognitive phenotypes from the Cambridge Neuropsychological Test Automated Battery. We showed these measures to be heritable by comparing the correlation in 100 monozygotic and 100 dizygotic twin pairs. The full battery was tested in ∼750 subjects, and for spatial and verbal recognition memory, we investigated a further 500 individuals to search for smaller genetic effects. We were unable to find any genome-wide significant associations with either SNPs or common copy number variants. Nor could we formally replicate any polymorphism that has been previously associated with cognition, although we found a weak signal of lower than expected P-values for variants in a set of 10 candidate genes. We additionally investigated SNPs in genomic loci that have been shown to harbor rare variants that associate with neuropsychiatric disorders, to see if they showed any suggestion of association when considered as a separate set. Only NRXN1 showed evidence of significant association with cognition. These results suggest that common genetic variation does not strongly influence cognition in healthy subjects and that cognitive measures do not represent a more tractable genetic trait than clinical endpoints such as schizophrenia. We discuss a possible role for rare variation in cognitive genomics.
In view of the increasing availability of commercial internet-based Personal Genome Testing (PGT), this study aimed to explore the reasons why people would consider taking such a test and how they would use the genetic risk information provided.
A self-completion questionnaire assessing public awareness and interest in PGT and motivational reasons for undergoing PGT was completed by 4,050 unselected adult volunteers from the UK-based TwinsUK register, aged 17 to 91 (response rate 62%). Only 13% of respondents were aware of the existence of PGT. After reading a brief summary about PGT, one in twenty participants (5%) were potentially interested at current prices (£250), however this proportion rose to half (50%) if the test was free of charge. Nearly all respondents who were interested in free PGT reported they would take the test to encourage them to adopt a healthier lifestyle if found to be at high genetic risk of a disease (93%). Around 4 in 5 respondents would have the test to convey genetic risk information to their children and a similar proportion felt that having a PGT would enable their doctor to monitor their health more closely. A TwinsUK research focus group also indicated that consumers would consult their GP to help interpret results of PGT.
This hypothetical study suggests that increasing publicity and decreasing costs of PGT may lead to increased uptake, driven in part by the general public's desire to monitor and improve their health. Although the future extent of the clinical utility of PGT is currently unknown, it is crucial that consumers are well informed about the current limitations of PGT. Our results suggest that health professionals will inevitably be required to respond to individuals who have undergone PGT. This has implications for health service providers regarding both cost and time.
Objectives. Musculoskeletal pain is reported commonly; however, the extent to which pain in individual body areas reflects the severity of site-specific pathology or a more generalized propensity to feel pain is uncertain. We used a classical twin design to examine the pattern of pain reporting at different body sites among monozygotic (MZ) and dizygotic (DZ) twins to assess its heritability and to examine evidence for a common underlying propensity to report musculoskeletal pain.
Methods. A well-characterized sample of female twins (TwinsUK cohort) was sent a questionnaire to determine their experience of pain in the neck and back, elbow, knee, thigh, hands or feet. The genetic contribution to pain reporting was assessed through univariate and multivariate analyses.
Results. Pain was reported with a prevalence of 17–46%, depending on the anatomical site. Univariate analysis indicated an underlying heritability for pain reporting at all sites of 28–71%. Pain reporting at different sites was modestly but uniformly correlated; a single factor accounted for 95% of the overall variance in pain reporting. The correlation for scores on this factor was 0.46 in MZ twins and 0.23 in DZ twins, corresponding to a ‘pain reporting factor’ heritability of 46% (95% CI 40%, 52%).
Conclusions. A single genetic factor underlies the propensity to report body pain at different musculoskeletal sites. These findings, which contrast with those for radiographic OA that is determined by genetic factors specific to each anatomical site, will inform the future search for therapeutic targets to treat pain in chronic degenerative diseases.
Osteoarthritis; Pain; Gene; Twin; Cholesky; Factor analysis; Multivariate; Pain reporting
Vitamin D may play a protective role in many diseases. Public health messages are advocating sun avoidance to reduce skin cancer risk but the potential deleterious effects of these recommendations for vitamin D metabolism have been poorly investigated.
We investigated the association between 25-hydroxy-vitamin D (25(OH)D), skin type and ultraviolet exposure in 1414 Caucasian females in the UK. Mean age of the cohort was 47 years (18–79) and mean 25(OH)D levels were 77 nmol/L (6–289). 25(OH)D levels were strongly associated with season of sampling with higher levels in the spring and summer months (p<0.0001). Light skin types (skin type 1 and 2) have lower levels of 25(OH)D (mean 71 nmol/L) compared to darker skin types (skin type 3 and 4) (mean 82 nmol/L) after adjusting for multiple confounders (p<0.0001). The trend for increasing risk of low vitamin D with fairer skin types was highly significant despite adjustment for all confounders (p = 0.001).
Contrary to previous studies across different ethnic backgrounds, this study within Caucasian UK females shows that fair skin types have lower levels of 25(OH)D compared to darker skin types with potential detrimental health effects. Public health campaigns advocating sun avoidance in fair skinned individuals may need to be revised in view of their risk of vitamin D deficiency.
We conducted a genome-wide association study for androgenic alopecia in 1,125 men and identified a newly associated locus at chromosome 20p11.22, confirmed in three independent cohorts (n = 1,650; OR = 1.60, P = 1.1 × 10−14 for rs1160312). The one man in seven who harbors risk alleles at both 20p11.22 and AR (encoding the androgen receptor) has a sevenfold-increased odds of androgenic alopecia (OR = 7.12, P = 3.7 × 10−15).
Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 × 10−4; Australia: P = 3.7 × 10−4). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 × 10−11). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 × 10−5). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.
Adiponectin is an insulin sensitizer in muscle and liver and low serum levels characterise obesity and insulin resistance. Eight tagging SNPs in the ADIPOQ gene and promoter were selected and association with serum adiponectin was tested in two independent samples of Caucasian females: the Chingford Study (n=808, mean age 62.8±5.9 years) and Twins UK (n=2718, mean age 47.4±12.6 years). In the Chingford cohort, −11391 G/A, −10066 G/A (rs182052), −7734 C/A (rs16861209), +276 G/T (rs1501299) and +3228 C/T (rs1063537) were significantly associated with fasting serum adiponectin (Ps=1.00 × 10−4 to 1.40 × 10−2). Associations with all except +3228 C/T were replicated in the Twins UK cohort (Ps=3.19 × 10−9 to 6.00 × 10−3). In Chingford subjects, the twelve most common 8-SNP haplotypes (freq. 1.90%) explained 2.85% (p=5.00 × 10−2) and in Twins UK subjects, the four most common 5-SNP haplotypes (freq. >5.00%) explained 1.66% of the variance (p=5.83 × 10−7). To investigate effects of −11391 G/A (rs17300539) and −11377 C/G (rs266729) on promoter activity, 1.2 kb of the ADIPOQ promoter region was cloned in a luciferase reporter plasmid and the four haplotypes were transfected in differentiated 3T3-L1 adipocytes. No significant allelic effects on promoter activity were found.
adiponectin; gene transfection; genetic epidemiology; metabolic syndrome; single nucleotide polymorphism