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1.  Biomarkers for Type 2 Diabetes and Impaired Fasting Glucose Using a Nontargeted Metabolomics Approach 
Diabetes  2013;62(12):4270-4276.
Using a nontargeted metabolomics approach of 447 fasting plasma metabolites, we searched for novel molecular markers that arise before and after hyperglycemia in a large population-based cohort of 2,204 females (115 type 2 diabetic [T2D] case subjects, 192 individuals with impaired fasting glucose [IFG], and 1,897 control subjects) from TwinsUK. Forty-two metabolites from three major fuel sources (carbohydrates, lipids, and proteins) were found to significantly correlate with T2D after adjusting for multiple testing; of these, 22 were previously reported as associated with T2D or insulin resistance. Fourteen metabolites were found to be associated with IFG. Among the metabolites identified, the branched-chain keto-acid metabolite 3-methyl-2-oxovalerate was the strongest predictive biomarker for IFG after glucose (odds ratio [OR] 1.65 [95% CI 1.39–1.95], P = 8.46 × 10−9) and was moderately heritable (h2 = 0.20). The association was replicated in an independent population (n = 720, OR 1.68 [ 1.34–2.11], P = 6.52 × 10−6) and validated in 189 twins with urine metabolomics taken at the same time as plasma (OR 1.87 [1.27–2.75], P = 1 × 10−3). Results confirm an important role for catabolism of branched-chain amino acids in T2D and IFG. In conclusion, this T2D-IFG biomarker study has surveyed the broadest panel of nontargeted metabolites to date, revealing both novel and known associated metabolites and providing potential novel targets for clinical prediction and a deeper understanding of causal mechanisms.
doi:10.2337/db13-0570
PMCID: PMC3837024  PMID: 23884885
2.  An atlas of genetic influences on human blood metabolites 
Nature genetics  2014;46(6):543-550.
Genome-wide association scans with high-throughput metabolic profiling provide unprecedented insights into how genetic variation influences metabolism and complex disease. Here we report the most comprehensive exploration of genetic loci influencing human metabolism to date, including 7,824 adult individuals from two European population studies. We report genome-wide significant associations at 145 metabolic loci and their biochemical connectivity regarding more than 400 metabolites in human blood. We extensively characterize the resulting in vivo blueprint of metabolism in human blood by integrating it with information regarding gene expression, heritability, overlap with known drug targets, previous association with complex disorders and inborn errors of metabolism. We further developed a database and web-based resources for data mining and results visualization. Our findings contribute to a greater understanding of the role of inherited variation in blood metabolic diversity, and identify potential new opportunities for pharmacologic development and disease understanding.
doi:10.1038/ng.2982
PMCID: PMC4064254  PMID: 24816252
3.  Human serum metabolic profiles are age dependent 
Aging Cell  2012;11(6):960-967.
Understanding the complexity of aging is of utmost importance. This can now be addressed by the novel and powerful approach of metabolomics. However, to date, only a few metabolic studies based on large samples are available. Here, we provide novel and specific information on age-related metabolite concentration changes in human homeostasis. We report results from two population-based studies: the KORA F4 study from Germany as a discovery cohort, with 1038 female and 1124 male participants (32–81 years), and the TwinsUK study as replication, with 724 female participants. Targeted metabolomics of fasting serum samples quantified 131 metabolites by FIA-MS/MS. Among these, 71/34 metabolites were significantly associated with age in women/men (BMI adjusted). We further identified a set of 13 independent metabolites in women (with P values ranging from 4.6 × 10−04 to 7.8 × 10−42, αcorr = 0.004). Eleven of these 13 metabolites were replicated in the TwinsUK study, including seven metabolite concentrations that increased with age (C0, C10:1, C12:1, C18:1, SM C16:1, SM C18:1, and PC aa C28:1), while histidine decreased. These results indicate that metabolic profiles are age dependent and might reflect different aging processes, such as incomplete mitochondrial fatty acid oxidation. The use of metabolomics will increase our understanding of aging networks and may lead to discoveries that help enhance healthy aging.
doi:10.1111/j.1474-9726.2012.00865.x
PMCID: PMC3533791  PMID: 22834969
age; aging; epidemiology; metabolomics; population-based study
4.  Metabolomic Identification of a Novel Pathway of Blood Pressure Regulation Involving Hexadecanedioate 
Hypertension  2015;66(2):422-429.
Supplemental Digital Content is available in the text.
High blood pressure is a major contributor to the global burden of disease and discovering novel causal pathways of blood pressure regulation has been challenging. We tested blood pressure associations with 280 fasting blood metabolites in 3980 TwinsUK females. Survival analysis for all-cause mortality was performed on significant independent metabolites (P<8.9×10−5). Replication was conducted in 2 independent cohorts KORA (n=1494) and Hertfordshire (n=1515). Three independent animal experiments were performed to establish causality: (1) blood pressure change after increasing circulating metabolite levels in Wistar–Kyoto rats; (2) circulating metabolite change after salt-induced blood pressure elevation in spontaneously hypertensive stroke-prone rats; and (3) mesenteric artery response to noradrenaline and carbachol in metabolite treated and control rats. Of the15 metabolites that showed an independent significant association with blood pressure, only hexadecanedioate, a dicarboxylic acid, showed concordant association with blood pressure (systolic BP: β [95% confidence interval], 1.31 [0.83–1.78], P=6.81×10−8; diastolic BP: 0.81 [0.5–1.11], P=2.96×10−7) and mortality (hazard ratio [95% confidence interval], 1.49 [1.08–2.05]; P=0.02) in TwinsUK. The blood pressure association was replicated in KORA and Hertfordshire. In the animal experiments, we showed that oral hexadecanedioate increased both circulating hexadecanedioate and blood pressure in Wistar–Kyoto rats, whereas blood pressure elevation with oral sodium chloride in hypertensive rats did not affect hexadecanedioate levels. Vascular reactivity to noradrenaline was significantly increased in mesenteric resistance arteries from hexadecanedioate-treated rats compared with controls, indicated by the shift to the left of the concentration–response curve (P=0.013). Relaxation to carbachol did not show any difference. Our findings indicate that hexadecanedioate is causally associated with blood pressure regulation through a novel pathway that merits further investigation.
doi:10.1161/HYPERTENSIONAHA.115.05544
PMCID: PMC4490909  PMID: 26034203
blood pressure; fatty acid synthases; hypertension; metabolomics; mortality
6.  A Genome-Wide Association Study Identifies Variants in Casein Kinase II (CSNK2A2) to be Associated with Leukocyte Telomere Length in a Punjabi Sikh Diabetic Cohort 
Background
Telomere length is a heritable trait and short telomere length has been associated with multiple chronic diseases. We investigated the relationship of relative leukocyte telomere length (RTL) with cardiometabolic risk and performed the first GWAS and meta-analysis to identify variants influencing RTL in a population of Sikhs from South Asia.
Methods and Results
Our results revealed a significant independent association of shorter RTL with type 2 diabetes (T2D) and heart disease. Our discovery GWAS (n=1,616) was followed by Stage 1 replication of 25 top signals (P<10−6) in an additional Sikhs (n=2,397). On combined discovery and Stage 1 meta-analysis (n= 4013), we identified a novel RTL locus at chromosome 16q21 represented by an intronic variant (rs74019828) in the CSNK2A2 gene (β −0.38, P=4.5×10−8). We further tested 3 top variants by genotyping in UKCVD (Caucasians n=2,952) for Stage 2. Next we performed in silico replication of 139 top signals (p<10−5) in UKTWIN, NHS, PLCO and MDACC (n=10,033) and joint meta-analysis (n=16,998). The observed signal in CSNK2A2 was confined to South Asians and could not be replicated in Caucasians due to significant difference in allele frequencies (P<0.001). CSNK2A2 phosphorylates TRF1 and plays an important role for regulation of telomere length homoeostasis.
Conclusions
By identification of a novel signal in telomere pathway genes, our study provides new molecular insight into the underlying mechanism that may regulate telomere length and its association with human aging and cardiometabolic pathophysiology.
doi:10.1161/CIRCGENETICS.113.000412
PMCID: PMC4106467  PMID: 24795349
telomere genetics; type 2 diabetes mellitus; Genome Wide Association Study; cardiovascular disease
7.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
Objective
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Methods
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
Results
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Conclusion
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
doi:10.1002/art.24524
PMCID: PMC4412885  PMID: 19479880
8.  Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region 
Annals of the Rheumatic Diseases  2012;72(3):427-436.
Background and objectives
Chronic widespread pain (CWP) is a common disorder affecting ∼10% of the general population and has an estimated heritability of 48–52%. In the first large-scale genome-wide association study (GWAS) meta-analysis, we aimed to identify common genetic variants associated with CWP.
Methods
We conducted a GWAS meta-analysis in 1308 female CWP cases and 5791 controls of European descent, and replicated the effects of the genetic variants with suggestive evidence for association in 1480 CWP cases and 7989 controls. Subsequently, we studied gene expression levels of the nearest genes in two chronic inflammatory pain mouse models, and examined 92 genetic variants previously described associated with pain.
Results
The minor C-allele of rs13361160 on chromosome 5p15.2, located upstream of chaperonin-containing-TCP1-complex-5 gene (CCT5) and downstream of FAM173B, was found to be associated with a 30% higher risk of CWP (minor allele frequency=43%; OR=1.30, 95% CI 1.19 to 1.42, p=1.2×10−8). Combined with the replication, we observed a slightly attenuated OR of 1.17 (95% CI 1.10 to 1.24, p=4.7×10−7) with moderate heterogeneity (I2=28.4%). However, in a sensitivity analysis that only allowed studies with joint-specific pain, the combined association was genome-wide significant (OR=1.23, 95% CI 1.14 to 1.32, p=3.4×10−8, I2=0%). Expression levels of Cct5 and Fam173b in mice with inflammatory pain were higher in the lumbar spinal cord, not in the lumbar dorsal root ganglions, compared to mice without pain. None of the 92 genetic variants previously described were significantly associated with pain (p>7.7×10−4).
Conclusions
We identified a common genetic variant on chromosome 5p15.2 associated with joint-specific CWP in humans. This work suggests that CCT5 and FAM173B are promising targets in the regulation of pain.
doi:10.1136/annrheumdis-2012-201742
PMCID: PMC3691951  PMID: 22956598
Gene Polymorphism; Fibromyalgis/Pain Syndromes; Epidemiology
9.  Parent-of-origin specific allelic associations among 106 genomic loci for age at menarche 
Perry, John RB | Day, Felix | Elks, Cathy E | Sulem, Patrick | Thompson, Deborah J | Ferreira, Teresa | He, Chunyan | Chasman, Daniel I | Esko, Tõnu | Thorleifsson, Gudmar | Albrecht, Eva | Ang, Wei Q | Corre, Tanguy | Cousminer, Diana L | Feenstra, Bjarke | Franceschini, Nora | Ganna, Andrea | Johnson, Andrew D | Kjellqvist, Sanela | Lunetta, Kathryn L | McMahon, George | Nolte, Ilja M | Paternoster, Lavinia | Porcu, Eleonora | Smith, Albert V | Stolk, Lisette | Teumer, Alexander | Tšernikova, Natalia | Tikkanen, Emmi | Ulivi, Sheila | Wagner, Erin K | Amin, Najaf | Bierut, Laura J | Byrne, Enda M | Hottenga, Jouke-Jan | Koller, Daniel L | Mangino, Massimo | Pers, Tune H | Yerges-Armstrong, Laura M | Zhao, Jing Hua | Andrulis, Irene L | Anton-Culver, Hoda | Atsma, Femke | Bandinelli, Stefania | Beckmann, Matthias W | Benitez, Javier | Blomqvist, Carl | Bojesen, Stig E | Bolla, Manjeet K | Bonanni, Bernardo | Brauch, Hiltrud | Brenner, Hermann | Buring, Julie E | Chang-Claude, Jenny | Chanock, Stephen | Chen, Jinhui | Chenevix-Trench, Georgia | Collée, J. Margriet | Couch, Fergus J | Couper, David | Coveillo, Andrea D | Cox, Angela | Czene, Kamila | D’adamo, Adamo Pio | Smith, George Davey | De Vivo, Immaculata | Demerath, Ellen W | Dennis, Joe | Devilee, Peter | Dieffenbach, Aida K | Dunning, Alison M | Eiriksdottir, Gudny | Eriksson, Johan G | Fasching, Peter A | Ferrucci, Luigi | Flesch-Janys, Dieter | Flyger, Henrik | Foroud, Tatiana | Franke, Lude | Garcia, Melissa E | García-Closas, Montserrat | Geller, Frank | de Geus, Eco EJ | Giles, Graham G | Gudbjartsson, Daniel F | Gudnason, Vilmundur | Guénel, Pascal | Guo, Suiqun | Hall, Per | Hamann, Ute | Haring, Robin | Hartman, Catharina A | Heath, Andrew C | Hofman, Albert | Hooning, Maartje J | Hopper, John L | Hu, Frank B | Hunter, David J | Karasik, David | Kiel, Douglas P | Knight, Julia A | Kosma, Veli-Matti | Kutalik, Zoltan | Lai, Sandra | Lambrechts, Diether | Lindblom, Annika | Mägi, Reedik | Magnusson, Patrik K | Mannermaa, Arto | Martin, Nicholas G | Masson, Gisli | McArdle, Patrick F | McArdle, Wendy L | Melbye, Mads | Michailidou, Kyriaki | Mihailov, Evelin | Milani, Lili | Milne, Roger L | Nevanlinna, Heli | Neven, Patrick | Nohr, Ellen A | Oldehinkel, Albertine J | Oostra, Ben A | Palotie, Aarno | Peacock, Munro | Pedersen, Nancy L | Peterlongo, Paolo | Peto, Julian | Pharoah, Paul DP | Postma, Dirkje S | Pouta, Anneli | Pylkäs, Katri | Radice, Paolo | Ring, Susan | Rivadeneira, Fernando | Robino, Antonietta | Rose, Lynda M | Rudolph, Anja | Salomaa, Veikko | Sanna, Serena | Schlessinger, David | Schmidt, Marjanka K | Southey, Mellissa C | Sovio, Ulla | Stampfer, Meir J | Stöckl, Doris | Storniolo, Anna M | Timpson, Nicholas J | Tyrer, Jonathan | Visser, Jenny A | Vollenweider, Peter | Völzke, Henry | Waeber, Gerard | Waldenberger, Melanie | Wallaschofski, Henri | Wang, Qin | Willemsen, Gonneke | Winqvist, Robert | Wolffenbuttel, Bruce HR | Wright, Margaret J | Boomsma, Dorret I | Econs, Michael J | Khaw, Kay-Tee | Loos, Ruth JF | McCarthy, Mark I | Montgomery, Grant W | Rice, John P | Streeten, Elizabeth A | Thorsteinsdottir, Unnur | van Duijn, Cornelia M | Alizadeh, Behrooz Z | Bergmann, Sven | Boerwinkle, Eric | Boyd, Heather A | Crisponi, Laura | Gasparini, Paolo | Gieger, Christian | Harris, Tamara B | Ingelsson, Erik | Järvelin, Marjo-Riitta | Kraft, Peter | Lawlor, Debbie | Metspalu, Andres | Pennell, Craig E | Ridker, Paul M | Snieder, Harold | Sørensen, Thorkild IA | Spector, Tim D | Strachan, David P | Uitterlinden, André G | Wareham, Nicholas J | Widen, Elisabeth | Zygmunt, Marek | Murray, Anna | Easton, Douglas F | Stefansson, Kari | Murabito, Joanne M | Ong, Ken K
Nature  2014;514(7520):92-97.
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality1. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation2,3, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P<5×10−8) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1/WDR25, MKRN3/MAGEL2 and KCNK9) demonstrating parent-of-origin specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and gamma-aminobutyric acid-B2 receptor signaling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
doi:10.1038/nature13545
PMCID: PMC4185210  PMID: 25231870
10.  Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans 
Huffman, Jennifer E. | Albrecht, Eva | Teumer, Alexander | Mangino, Massimo | Kapur, Karen | Johnson, Toby | Kutalik, Zoltán | Pirastu, Nicola | Pistis, Giorgio | Lopez, Lorna M. | Haller, Toomas | Salo, Perttu | Goel, Anuj | Li, Man | Tanaka, Toshiko | Dehghan, Abbas | Ruggiero, Daniela | Malerba, Giovanni | Smith, Albert V. | Nolte, Ilja M. | Portas, Laura | Phipps-Green, Amanda | Boteva, Lora | Navarro, Pau | Johansson, Asa | Hicks, Andrew A. | Polasek, Ozren | Esko, Tõnu | Peden, John F. | Harris, Sarah E. | Murgia, Federico | Wild, Sarah H. | Tenesa, Albert | Tin, Adrienne | Mihailov, Evelin | Grotevendt, Anne | Gislason, Gauti K. | Coresh, Josef | D'Adamo, Pio | Ulivi, Sheila | Vollenweider, Peter | Waeber, Gerard | Campbell, Susan | Kolcic, Ivana | Fisher, Krista | Viigimaa, Margus | Metter, Jeffrey E. | Masciullo, Corrado | Trabetti, Elisabetta | Bombieri, Cristina | Sorice, Rossella | Döring, Angela | Reischl, Eva | Strauch, Konstantin | Hofman, Albert | Uitterlinden, Andre G. | Waldenberger, Melanie | Wichmann, H-Erich | Davies, Gail | Gow, Alan J. | Dalbeth, Nicola | Stamp, Lisa | Smit, Johannes H. | Kirin, Mirna | Nagaraja, Ramaiah | Nauck, Matthias | Schurmann, Claudia | Budde, Kathrin | Farrington, Susan M. | Theodoratou, Evropi | Jula, Antti | Salomaa, Veikko | Sala, Cinzia | Hengstenberg, Christian | Burnier, Michel | Mägi, Reedik | Klopp, Norman | Kloiber, Stefan | Schipf, Sabine | Ripatti, Samuli | Cabras, Stefano | Soranzo, Nicole | Homuth, Georg | Nutile, Teresa | Munroe, Patricia B. | Hastie, Nicholas | Campbell, Harry | Rudan, Igor | Cabrera, Claudia | Haley, Chris | Franco, Oscar H. | Merriman, Tony R. | Gudnason, Vilmundur | Pirastu, Mario | Penninx, Brenda W. | Snieder, Harold | Metspalu, Andres | Ciullo, Marina | Pramstaller, Peter P. | van Duijn, Cornelia M. | Ferrucci, Luigi | Gambaro, Giovanni | Deary, Ian J. | Dunlop, Malcolm G. | Wilson, James F. | Gasparini, Paolo | Gyllensten, Ulf | Spector, Tim D. | Wright, Alan F. | Hayward, Caroline | Watkins, Hugh | Perola, Markus | Bochud, Murielle | Kao, W. H. Linda | Caulfield, Mark | Toniolo, Daniela | Völzke, Henry | Gieger, Christian | Köttgen, Anna | Vitart, Veronique
PLoS ONE  2015;10(3):e0119752.
We tested for interactions between body mass index (BMI) and common genetic variants affecting serum urate levels, genome-wide, in up to 42569 participants. Both stratified genome-wide association (GWAS) analyses, in lean, overweight and obese individuals, and regression-type analyses in a non BMI-stratified overall sample were performed. The former did not uncover any novel locus with a major main effect, but supported modulation of effects for some known and potentially new urate loci. The latter highlighted a SNP at RBFOX3 reaching genome-wide significant level (effect size 0.014, 95% CI 0.008-0.02, Pinter= 2.6 x 10-8). Two top loci in interaction term analyses, RBFOX3 and ERO1LB-EDARADD, also displayed suggestive differences in main effect size between the lean and obese strata. All top ranking loci for urate effect differences between BMI categories were novel and most had small magnitude but opposite direction effects between strata. They include the locus RBMS1-TANK (men, Pdifflean-overweight= 4.7 x 10-8), a region that has been associated with several obesity related traits, and TSPYL5 (men, Pdifflean-overweight= 9.1 x 10-8), regulating adipocytes-produced estradiol. The top-ranking known urate loci was ABCG2, the strongest known gout risk locus, with an effect halved in obese compared to lean men (Pdifflean-obese= 2 x 10-4). Finally, pathway analysis suggested a role for N-glycan biosynthesis as a prominent urate-associated pathway in the lean stratum. These results illustrate a potentially powerful way to monitor changes occurring in obesogenic environment.
doi:10.1371/journal.pone.0119752
PMCID: PMC4374966  PMID: 25811787
11.  A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans 
Nature communications  2014;5:4871.
The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 standard deviations (standard error (s.e.=0.27) per minor allele (p-value=8.0×10−8)) discovered in 3202 individuals with low read-depth, whole genome sequence. We replicate this in 12831 participants from five additional samples of Northern and Southern European origin (−1.0 standard deviation (s.e.=0.173), p-value=7.32×10−9). This is consistent with an effect between 0.5 and 1.5mmol/L dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.
doi:10.1038/ncomms5871
PMCID: PMC4167609  PMID: 25225788
Whole genome sequence; triglycerides; APOC3
12.  Metabolomic study of carotid–femoral pulse-wave velocity in women 
Journal of Hypertension  2015;33(4):791-796.
Objective:
Carotid–femoral pulse-wave velocity (PWV) is a measure of aortic stiffness that is strongly associated with increased risk of cardiovascular morbidity and mortality. The aim of the current study was to identify the molecular markers and the pathways involved in differences in PWV in women, in order to further understand the regulation of arterial stiffening.
Methods:
A total of 280 known metabolites were measured in 1797 female twins (age range: 18–84 years) not on any antihypertensive medication. Metabolites associated with PWV (after adjustment for age, BMI, metabolite batch, and family relatedness) were entered into a backward linear regression. Transcriptomic analyses were further performed on the top compounds identified.
Results:
Twelve metabolites were associated with PWV (P < 1.8 × 10−4). One of the most strongly associated metabolites was uridine, which was not associated with blood pressure (BP) and traditional risk factors but correlated significantly with the gene-expression levels of the purinergic receptor P2RY2 (Beta = −0.010, SE = 0.003, P = 0.007), suggesting that it may play a role in regulating endothelial nitric oxide synthase phosphorylation. On the other hand, phenylacetylglutamine was strongly associated with both PWV and BP.
Conclusion:
Circulating levels of uridine, phenylacetylglutamine, and serine appear strongly correlated with PWV in women.
doi:10.1097/HJH.0000000000000467
PMCID: PMC4354457  PMID: 25490711
biomarkers; metabolomics; pulse-wave velocity
13.  The role of heredity in determining central retinal thickness 
The British Journal of Ophthalmology  2007;91(9):1143-1147.
Aims
To examine the relative roles of genetic and environmental factors in central retinal thickness, by performing a classical twin study.
Methods
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).
Results
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.
Conclusion
Genetic factors appear to play an important role in CRT, with a heritability estimate of 0.90.
doi:10.1136/bjo.2007.114215
PMCID: PMC1954930  PMID: 17360735
14.  Genomewide linkage scan of hand osteoarthritis in female twin pairs showing replication of quantitative trait loci on chromosomes 2 and 19 
Annals of the Rheumatic Diseases  2006;66(5):623-627.
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.
doi:10.1136/ard.2006.060236
PMCID: PMC1954638  PMID: 17127684
15.  Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration 
Annals of the Rheumatic Diseases  2006;66(4):476-480.
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.
doi:10.1136/ard.2006.059188
PMCID: PMC1856061  PMID: 17114192
16.  Quantitative variability of 342 plasma proteins in a human twin population 
Molecular Systems Biology  2015;11(2):786.
The degree and the origins of quantitative variability of most human plasma proteins are largely unknown. Because the twin study design provides a natural opportunity to estimate the relative contribution of heritability and environment to different traits in human population, we applied here the highly accurate and reproducible SWATH mass spectrometry technique to quantify 1,904 peptides defining 342 unique plasma proteins in 232 plasma samples collected longitudinally from pairs of monozygotic and dizygotic twins at intervals of 2–7 years, and proportioned the observed total quantitative variability to its root causes, genes, and environmental and longitudinal factors. The data indicate that different proteins show vastly different patterns of abundance variability among humans and that genetic control and longitudinal variation affect protein levels and biological processes to different degrees. The data further strongly suggest that the plasma concentrations of clinical biomarkers need to be calibrated against genetic and temporal factors. Moreover, we identified 13 cis-SNPs significantly influencing the level of specific plasma proteins. These results therefore have immediate implications for the effective design of blood-based biomarker studies.
doi:10.15252/msb.20145728
PMCID: PMC4358658  PMID: 25652787
heritability; longitudinal variability; plasma biomarkers; SWATH-MS; twin study
17.  Predicting genome-wide DNA methylation using methylation marks, genomic position, and DNA regulatory elements 
Genome Biology  2015;16(1):14.
Background
Recent assays for individual-specific genome-wide DNA methylation profiles have enabled epigenome-wide association studies to identify specific CpG sites associated with a phenotype. Computational prediction of CpG site-specific methylation levels is critical to enable genome-wide analyses, but current approaches tackle average methylation within a locus and are often limited to specific genomic regions.
Results
We characterize genome-wide DNA methylation patterns, and show that correlation among CpG sites decays rapidly, making predictions solely based on neighboring sites challenging. We built a random forest classifier to predict methylation levels at CpG site resolution using features including neighboring CpG site methylation levels and genomic distance, co-localization with coding regions, CpG islands (CGIs), and regulatory elements from the ENCODE project. Our approach achieves 92% prediction accuracy of genome-wide methylation levels at single-CpG-site precision. The accuracy increases to 98% when restricted to CpG sites within CGIs and is robust across platform and cell-type heterogeneity. Our classifier outperforms other types of classifiers and identifies features that contribute to prediction accuracy: neighboring CpG site methylation, CGIs, co-localized DNase I hypersensitive sites, transcription factor binding sites, and histone modifications were found to be most predictive of methylation levels.
Conclusions
Our observations of DNA methylation patterns led us to develop a classifier to predict DNA methylation levels at CpG site resolution with high accuracy. Furthermore, our method identified genomic features that interact with DNA methylation, suggesting mechanisms involved in DNA methylation modification and regulation, and linking diverse epigenetic processes.
Electronic supplementary material
The online version of this article (doi:10.1186/s13059-015-0581-9) contains supplementary material, which is available to authorized users.
doi:10.1186/s13059-015-0581-9
PMCID: PMC4389802  PMID: 25616342
18.  An integrated epigenomic analysis for type 2 diabetes susceptibility loci in monozygotic twins 
Nature Communications  2014;5:5719.
DNA methylation has a great potential for understanding the aetiology of common complex traits such as Type 2 diabetes (T2D). Here we perform genome-wide methylated DNA immunoprecipitation sequencing (MeDIP-seq) in whole-blood-derived DNA from 27 monozygotic twin pairs and follow up results with replication and integrated omics analyses. We identify predominately hypermethylated T2D-related differentially methylated regions (DMRs) and replicate the top signals in 42 unrelated T2D cases and 221 controls. The strongest signal is in the promoter of the MALT1 gene, involved in insulin and glycaemic pathways, and related to taurocholate levels in blood. Integrating the DNA methylome findings with T2D GWAS meta-analysis results reveals a strong enrichment for DMRs in T2D-susceptibility loci. We also detect signals specific to T2D-discordant twins in the GPR61 and PRKCB genes. These replicated T2D associations reflect both likely causal and consequential pathways of the disease. The analysis indicates how an integrated genomics and epigenomics approach, utilizing an MZ twin design, can provide pathogenic insights as well as potential drug targets and biomarkers for T2D and other complex traits.
Type 2 diabetes (T2D) is a highly heterogeneous disease with a strong genetic component. Here the authors examine genome-wide methylation patterns in T2D-discordant, T2D-concordant and healthy concordant monozygotic twin pairs, and identify DNA methylation signals that may represent new biomarkers or drug targets for T2D.
doi:10.1038/ncomms6719
PMCID: PMC4284644  PMID: 25502755
19.  Germline Genetic Contributions to Risk for Esophageal Adenocarcinoma, Barrett’s Esophagus, and Gastroesophageal Reflux 
Background
Esophageal adenocarcinoma (EA) is an increasingly common cancer with poor survival. Barrett’s esophagus (BE) is the main precursor to EA, and every year 0.12% to 0.5% of BE patients progress to EA. BE typically arises on a background of chronic gastroesophageal reflux (GERD), one of the risk factors for EA.
Methods
We used genome-wide association data to investigate the genetic architecture underlying GERD, BE, and EA. We applied a method to estimate the variance explained (array heritability, h2 g) and the genetic correlation (rg) between GERD, BE, and EA by considering all single nucleotide polymorphisms (SNPs) simultaneously. We also estimated the polygenic overlap between GERD, BE, and EA using a prediction approach. All tests were two-sided, except in the case of variance-explained estimation where one-sided tests were used.
Results
We estimated a statistically significant genetic variance explained for BE (h2 g = 35%; standard error [SE] = 6%; one-sided P = 1 × 10−9) and for EA (h2 g = 25 %; SE = 5%; one-sided P = 2 × 10−7). The genetic correlation between BE and EA was found to be high (rg = 1.0; SE = 0.37). We also estimated a statistically significant polygenic overlap between BE and EA (one-sided P = 1 × 10−6), which suggests, together with the high genetic correlation, that shared genes underlie the development of BE and EA. Conversely, no statistically significant results were obtained for GERD.
Conclusions
We have demonstrated that risk to BE and EA is influenced by many germline genetic variants of small effect and that shared polygenic effects contribute to risk of these two diseases.
doi:10.1093/jnci/djt303
PMCID: PMC3833931  PMID: 24168968
20.  Heritability of objectively assessed daily physical activity and sedentary behavior1234 
Background: Twin and family studies that estimated the heritability of daily physical activity have been limited by poor measurement quality and a small sample size.
Objective: We examined the heritability of daily physical activity and sedentary behavior assessed objectively by using combined heart rate and movement sensing in a large twin study.
Design: Physical activity traits were assessed in daily life for a mean (±SD) 6.7 ± 1.1 d in 1654 twins from 420 monozygotic and 352 dizygotic same-sex twin pairs aged 56.3 ± 10.4 y with body mass index (in kg/m2) of 26.1 ± 4.8. We estimated the average daily movement, physical activity energy expenditure, and time spent in moderate-to-vigorous intensity physical activity and sedentary behavior from heart rate and acceleration data. We used structural equation modeling to examine the contribution of additive genetic, shared environmental, and unique environmental factors to between-individual variation in traits.
Results: Additive genetic factors (ie, heritability) explained 47% of the variance in physical activity energy expenditure (95% CI: 23%, 53%) and time spent in moderate-to-vigorous intensity physical activity (95% CI: 29%, 54%), 35% of the variance in acceleration of the trunk (95% CI: 0%, 44%), and 31% of the variance in the time spent in sedentary behavior (95% CI: 9%, 51%). The remaining variance was predominantly explained by unique environmental factors and random error, whereas shared environmental factors played only a marginal role for all traits with a range of 0–15%.
Conclusions: The between-individual variation in daily physical activity and sedentary behavior is mainly a result of environmental influences. Nevertheless, genetic factors explain up to one-half of the variance, suggesting that innate biological processes may be driving some of our daily physical activity.
doi:10.3945/ajcn.113.069849
PMCID: PMC3798083  PMID: 24047914
21.  Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect 
European Journal of Human Genetics  2013;21(10):1163-1168.
Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10−61) than father–offspring correlation (r=0.33; P-value=7.01 × 10−5), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10−5). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10−30) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10−23) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10−10). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.
doi:10.1038/ejhg.2012.303
PMCID: PMC3778341  PMID: 23321625
telomere length; heritability; paternal age effect
22.  Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes 
Yaghootkar, Hanieh | Lamina, Claudia | Scott, Robert A. | Dastani, Zari | Hivert, Marie-France | Warren, Liling L. | Stancáková, Alena | Buxbaum, Sarah G. | Lyytikäinen, Leo-Pekka | Henneman, Peter | Wu, Ying | Cheung, Chloe Y.Y. | Pankow, James S. | Jackson, Anne U. | Gustafsson, Stefan | Zhao, Jing Hua | Ballantyne, Christie M. | Xie, Weijia | Bergman, Richard N. | Boehnke, Michael | el Bouazzaoui, Fatiha | Collins, Francis S. | Dunn, Sandra H. | Dupuis, Josee | Forouhi, Nita G. | Gillson, Christopher | Hattersley, Andrew T. | Hong, Jaeyoung | Kähönen, Mika | Kuusisto, Johanna | Kedenko, Lyudmyla | Kronenberg, Florian | Doria, Alessandro | Assimes, Themistocles L. | Ferrannini, Ele | Hansen, Torben | Hao, Ke | Häring, Hans | Knowles, Joshua W. | Lindgren, Cecilia M. | Nolan, John J. | Paananen, Jussi | Pedersen, Oluf | Quertermous, Thomas | Smith, Ulf | Lehtimäki, Terho | Liu, Ching-Ti | Loos, Ruth J.F. | McCarthy, Mark I. | Morris, Andrew D. | Vasan, Ramachandran S. | Spector, Tim D. | Teslovich, Tanya M. | Tuomilehto, Jaakko | van Dijk, Ko Willems | Viikari, Jorma S. | Zhu, Na | Langenberg, Claudia | Ingelsson, Erik | Semple, Robert K. | Sinaiko, Alan R. | Palmer, Colin N.A. | Walker, Mark | Lam, Karen S.L. | Paulweber, Bernhard | Mohlke, Karen L. | van Duijn, Cornelia | Raitakari, Olli T. | Bidulescu, Aurelian | Wareham, Nick J. | Laakso, Markku | Waterworth, Dawn M. | Lawlor, Debbie A. | Meigs, James B. | Richards, J. Brent | Frayling, Timothy M.
Diabetes  2013;62(10):3589-3598.
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics–based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26–0.35) increase in fasting insulin, a 0.34-SD (0.30–0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47–2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI −0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (−0.20 SD; 95% CI −0.38 to −0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75–1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: −0.03 SD; 95% CI −0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95–1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
doi:10.2337/db13-0128
PMCID: PMC3781444  PMID: 23835345
23.  Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction 
Background
The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to further characterize the contribution of rare and common coding variation in SCN5A to cardiac conduction.
Methods and Results
In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study (CHARGE), we performed targeted exonic sequencing of SCN5A (n=3699, European-ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, NHLBI’s Exome Sequencing Project (ESP, n=607) and the UK10K (n=1275) and by examining ESP African-ancestry participants (N=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African-ancestry participants (P=1.3×10−3). Three common variants were associated with PR and/or QRS interval duration among European-ancestry participants and one among African-ancestry participants. These included two well-known missense variants; rs1805124 (H558R) was associated with PR and QRS shortening in European-ancestry participants (P=6.25×10−4 and P=5.2×10−3 respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10−3). Among European-ancestry participants, two novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10−7 and P=2.69×10−4 respectively), and rs6599230 was associated with PR shortening (P=2.67×10−5).
Conclusions
By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.
doi:10.1161/CIRCGENETICS.113.000098
PMCID: PMC4177904  PMID: 24951663
PR interval; QRS interval; genetics; sequencing; cohort
24.  A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans 
Nature Communications  2014;5:4871.
The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency ~0.25% (UK)) associated with plasma triglyceride (TG) levels (−1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 10−8)) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (−1.0 s.d. (s.e.=0.173), P-value=7.32 × 10−9). This is consistent with an effect between 0.5 and 1.5 mmol l−1 dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.
Population-based genome sequencing provides an increasingly rich resource for the identification of low-frequency, large effect variants associated with clinically important phenotypes. Timpson et al. use UK10K data to identify a variant of the APOC3 gene strongly associated with plasma triglyceride levels.
doi:10.1038/ncomms5871
PMCID: PMC4167609  PMID: 25225788
25.  Epigenome-Wide DNA Methylation in Hearing Ability: New Mechanisms for an Old Problem 
PLoS ONE  2014;9(9):e105729.
Epigenetic regulation of gene expression has been shown to change over time and may be associated with environmental exposures in common complex traits. Age-related hearing impairment is a complex disorder, known to be heritable, with heritability estimates of 57–70%. Epigenetic regulation might explain the observed difference in age of onset and magnitude of hearing impairment with age. Epigenetic epidemiology studies using unrelated samples can be limited in their ability to detect small effects, and recent epigenetic findings in twins underscore the power of this well matched study design. We investigated the association between venous blood DNA methylation epigenome-wide and hearing ability. Pure-tone audiometry (PTA) and Illumina HumanMethylation array data were obtained from female twin volunteers enrolled in the TwinsUK register. Two study groups were explored: first, an epigenome-wide association scan (EWAS) was performed in a discovery sample (n = 115 subjects, age range: 47–83 years, Illumina 27 k array), then replication of the top ten associated probes from the discovery EWAS was attempted in a second unrelated sample (n = 203, age range: 41–86 years, Illumina 450 k array). Finally, a set of monozygotic (MZ) twin pairs (n = 21 pairs) within the discovery sample (Illumina 27 k array) was investigated in more detail in an MZ discordance analysis. Hearing ability was strongly associated with DNA methylation levels in the promoter regions of several genes, including TCF25 (cg01161216, p = 6.6×10−6), FGFR1 (cg15791248, p = 5.7×10−5) and POLE (cg18877514, p = 6.3×10−5). Replication of these results in a second sample confirmed the presence of differential methylation at TCF25 (p(replication) = 6×10−5) and POLE (p(replication) = 0.016). In the MZ discordance analysis, twins' intrapair difference in hearing ability correlated with DNA methylation differences at ACP6 (cg01377755, r = −0.75, p = 1.2×10−4) and MEF2D (cg08156349, r = −0.75, p = 1.4×10−4). Examination of gene expression in skin, suggests an influence of differential methylation on expression, which may account for the variation in hearing ability with age.
doi:10.1371/journal.pone.0105729
PMCID: PMC4153547  PMID: 25184702

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