Genetic determinants of hair and eye colours in the Scottish and Danish populations

<p>Abstract</p> <p>Background</p> <p>Eye and hair colour is highly variable in the European population, and is largely genetically determined. Both linkage and association studies have previously been used to identify candidate genes underlying this variation. Many of the genes found were previously known as underlying mutant mouse phenotypes or human genetic disease, but others, previously unsuspected as pigmentation genes, have also been discovered.</p> <p>Results</p> <p>We assayed the hair of a population of individuals of Scottish origin using tristimulus colorimetry, in order to produce a quantitative measure of hair colour. Cluster analysis of this data defined two groups, with overlapping borders, which corresponded to visually assessed dark versus red/light hair colour. The Danish population was assigned into categorical hair colour groups. Both cohorts were also assessed for eye colour. DNA from the Scottish group was genotyped at SNPs in 33 candidate genes, using 384 SNPs identified by HapMap as representatives of each gene. Associations found between SNPs and colorimetric hair data and eye colour categories were replicated in a cohort of the Danish population. The Danish population was also genotyped with SNPs in 4 previously described pigmentation genes. We found replicable associations of hair colour with the <it>KITLG </it>and <it>OCA2 </it>genes. <it>MC1R </it>variation correlated, as expected, with the red dimension of colorimetric hair colour in Scots. The Danish analysis excluded those with red hair, and no associations were found with <it>MC1R </it>in this group, emphasising that <it>MC1R </it>regulates the colour rather than the intensity of pigmentation. A previously unreported association with the <it>HPS3 </it>gene was seen in the Scottish population. However, although this replicated in the smaller cohort of the Danish population, no association was seen when the whole study population was analysed.</p> <p>Conclusions</p> <p>We have found novel associations with SNPs in known pigmentation genes and colorimetrically assessed hair colour in a Scottish and a Danish population.</p

Heritability and circulating concentrations of pregnancy-associated plasma protein-A and stanniocalcin-2 in elderly monozygotic and dizygotic twins

IntroductionPregnancy-associated plasma protein-A (PAPP-A) is an IGF-activating enzyme suggested to influence aging-related diseases. However, knowledge on serum PAPP-A concentration and regulation in elderly subjects is limited. Therefore, we measured serum PAPP-A in elderly same-sex monozygotic (MZ) and dizygotic (DZ) twins, as this allowed us to describe the age-relationship of PAPP-A, and to test the hypothesis that serum PAPP-A concentrations are genetically determined. As PAPP-A is functionally related to stanniocalcin-2 (STC2), an endogenous PAPP-A inhibitor, we included measurements on STC2 as well as IGF-I and IGF-II.MethodsThe twin cohort contained 596 subjects (250 MZ twins, 346 DZ twins), whereof 33% were males. The age ranged from 73.2 to 94.3 (mean 78.8) years. Serum was analyzed for PAPP-A, STC2, IGF-I, and IGF-II by commercial immunoassays.ResultsIn the twin cohort, PAPP-A increased with age (r=0.19; P&lt;0.05), whereas IGF-I decreased (r=-0.12; P&lt;0.05). Neither STC2 nor IGF-II showed any age relationship. When analyzed according to sex, PAPP-A correlated positively with age in males (r=0.18; P&lt;0.05) and females (r=0.25; P&lt;0.01), whereas IGF-I correlated inversely in females only (r=-0.15; P&lt;0.01). Males had higher levels of PAPP-A (29%), STC2 (18%) and IGF-I (19%), whereas serum IGF-II was 28% higher in females (all P&lt;0.001). For all four proteins, within-pair correlations were significantly higher for MZ twins than for DZ twins, and they demonstrated substantial and significant heritability, which after adjustment for age and sex averaged 59% for PAPP-A, 66% for STC2, 58% for IGF-I, and 52% for IGF-II.DiscussionThis twin study confirms our hypothesis that the heritability of PAPP-A serum concentrations is substantial, and the same is true for STC2. As regards the age relationship, PAPP-A increases with age, whereas STC2 remains unchanged, thereby supporting the idea that the ability of STC2 to inhibit PAPP-A enzymatic activity decreases with increasing age

Differential regulation of the DNA methylome in adults born during the Great Chinese Famine in 1959-1961

Background: Extensive epidemiological studies have established the association between exposure to early-life adversity and health status and diseases in adults. Epigenetic regulation is considered as a key mediator for this phenomenon but analysis on humans is sparse. The Great Chinese Famine lasting from 1958 to 1961 is a natural string of disasters offering a precious opportunity for elucidating the underlying epigenetic mechanism of the long-term effect of early adversity. Methods: Using a high-throughput array platform for DNA methylome profiling, we conducted a case-control epigenome-wide association study on early-life exposure to Chinese famine in 79 adults born during 1959-1961 and compared to 105 unexposed subjects born 1963-1964. Results: The single CpG site analysis of whole epigenome revealed a predominant pattern of decreased DNA methylation levels associated with fetal exposure to famine. Four CpG sites were detected with p < 1e-06 (linked to EHMT1, CNR1, UBXN7 and ESM1 genes), 16 CpGs detected with 1e-06 < p < 1e-05 and 157 CpGs with 1e-05 < p < 1e-04, with a predominant pattern of hypomethylation. Functional annotation to genes and their enriched biological pathways mainly involved neurodevelopment, neuropsychological disorders and metabolism. Multiple sites analysis detected two top-rank differentially methylated regions harboring RNF39 on chromosome 6 and PTPRN2 on chromosome 7, both showing epigenetic association with stress-related conditions. Conclusion: Early-life exposure to famine could mediate DNA methylation regulations that persist into adulthood with broad impacts in the activities of genes and biological pathways. Results from this study provide new clues to the epigenetic embedding of early-life adversity and its impacts on adult health.Peer reviewe

Global Gene Expression Profiling of Body-Mass Index in Middle-Aged Danish Twins

Objective: The body mass index (BMI) measured as weight in relation to height is an important monitor for obesity and diabetes, with individual variation under control by genetic and environmental factors. In transcriptome-wide association studies on BMI, the genetic contribution calls for controlling of genetic confounding that affects both BMI and gene expression. We performed a global gene expression profiling of BMI on peripheral blood cells using monozygotic twins for efficient handling of genetic make-ups. Methods: We applied a generalized association method to genome-wide gene expression data on 229 pairs of monozygotic twins (age 56-80 years) for detecting diverse patterns of correlation between BMI and gene expression. Results: We detected seven probes associated with BMI with p<1e-04, among them two probes with p<1e-05 (p=2.83e-06 AAK1; p=7.83e-06 LILRA3). In total, the analysis found 1579 probes with nominal p<0.05. Biological pathway analysis of enriched pathways found 50 KEGG and 45 Reactome pathways (FDR<0.05). The identified top functional pathways included immune function, JAK-STAT signalling, insulin signalling and regulation of energy metabolism. Conclusion: This transcriptome-wide association study using monozygotic twins and generalized correlation identified differentially expressed genes and a broad spectrum of enriched biological pathways that may implicate metabolic health

Novel DNA methylation marker discovery by assumption-free genome-wide association analysis of cognitive function in twins

Privileged by rapid increase in available epigenomic data, epigenome-wide association studies (EWAS) are to make a profound contribution to understand the molecular mechanism of DNA methylation in cognitive aging. Current statistical methods used in EWAS are dominated by models based on multiple assumptions, for example, linear relationship between molecular profiles and phenotype, normal distribution for the methylation data and phenotype. In this study, we applied an assumption-free method, the generalized correlation coefficient (GCC), and compare it to linear models, namely the linear mixed model and kinship model. We use DNA methylation associated with a cognitive score in 400 and 206 twins as discovery and replication samples respectively. DNA methylation associated with cognitive function using GCC, linear mixed model, and kinship model, identified 65 CpGs (p < 1e-04) from discovery sample displaying both nonlinear and linear correlations. Replication analysis successfully replicated 9 of these top CpGs. When combining results of GCC and linear models to cover diverse patterns of relationships, we identified genes like KLHDC4, PAPSS2, and MRPS18B as well as pathways including focal adhesion, axon guidance, and some neurological signaling. Genomic region-based analysis found 15 methylated regions harboring 11 genes, with three verified in gene expression analysis, also the 11 genes were related to top functional clusters including neurohypophyseal hormone and maternal aggressive behaviors. The GCC approach detects valuable methylation sites missed by traditional linear models. A combination of methylation markers from GCC and linear models enriched biological pathways sensible in neurological function that could implicate cognitive performance and cognitive aging.Peer reviewe

Genetic and environmental determinants of O6-methylguanine DNA-methyltransferase (MGMT) gene methylation: a 10-year longitudinal study of Danish twins

Background: Epigenetic inactivation of O6-methylguanine DNA-methyltransferase (MGMT) is associated with increased sensitivity to alkylating chemotherapeutic agents in glioblastoma patients. The genetic background underlying MGMT gene methylation may explain individual differences in treatment response and provide a clue to a personalized treatment strategy. Making use of the longitudinal twin design, we aimed, for the first time, to estimate the genetic contributions to MGMT methylation in a Danish twin cohort. Methods: DNA-methylation from whole blood (18 monozygotic (MZ) and 25 dizygotic (DZ) twin pairs) repeated 10 years apart from the Longitudinal Study of Aging Danish Twins (LSADT) were used to search for genetic and environmental contributions to DNA-methylation at 170 CpG sites of across the MGMT gene. Both univariate and bivariate twin models were applied. The intraclass correlations, performed on cross-sectional data (246 MZ twin pairs) from an independent study population, the Middle-Aged Danish Twins (MADT), were used to assess the genetic influence at each CpG site of MGMT for replication. Results: Univariate twin model revealed twelve CpG sites showing significantly high heritability at intake (wave 1, h2 > 0.43), and seven CpG sites with significant heritability estimates at end of follow-up (wave 2, h2 > 0.5). There were six significant CpG sites, located at the gene body region, that overlapped among the two waves (h2 > 0.5), of which five remained significant in the bivariate twin model, which was applied to both waves. Within MZ pair correlation in these six CpGs from MADT demarks top level of genetic influence. There were 11 CpGs constantly have substantial common environmental component over the 10 years. Conclusions: We have identified 6 CpG sites linked to the MGMT gene with strong and persistent genetic control based on their DNA methylation levels. The genetic basis of MGMT gene methylation could help to explain individual differences in glioblastoma treatment response and most importantly, provide references for mapping the methylation Quantitative Trait Loci (meQTL) underlying the genetic regulation.Peer reviewe

Global Gene Expression Profiling and Transcription Factor Network Analysis of Cognitive Aging in Monozygotic Twins

Cognitive aging is one of the major problems worldwide, especially as people get older. This study aimed to perform global gene expression profiling of cognitive function to identify associated genes and pathways and a novel transcriptional regulatory network analysis to identify important regulons. We performed single transcript analysis on 400 monozygotic twins using an assumption-free generalized correlation coefficient (GCC), linear mixed-effect model (LME) and kinship model and identified six probes (one significant at the standard FDR < 0.05 while the other results were suggestive with 0.18 ≤ FDR ≤ 0.28). We combined the GCC and linear model results to cover diverse patterns of relationships, and meaningful and novel genes like APOBEC3G, H6PD, SLC45A1, GRIN3B, and PDE4D were detected. Our exploratory study showed the downregulation of all these genes with increasing cognitive function or vice versa except the SLC45A1 gene, which was upregulated with increasing cognitive function. Linear models found only H6PD and SLC45A1, the other genes were captured by GCC. Significant functional pathways (FDR < 3.95e-10) such as focal adhesion, ribosome, cysteine and methionine metabolism, Huntington's disease, eukaryotic translation elongation, nervous system development, influenza infection, metabolism of RNA, and cell cycle were identified. A total of five regulons (FDR< 1.3e-4) were enriched in a transcriptional regulatory analysis in which CTCF and REST were activated and SP3, SRF, and XBP1 were repressed regulons. The genome-wide transcription analysis using both assumption-free GCC and linear models identified important genes and biological pathways implicated in cognitive performance, cognitive aging, and neurological diseases. Also, the regulatory network analysis revealed significant activated and repressed regulons on cognitive function.Peer reviewe