F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes.

OBJECTIVE: F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored. METHODS: We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed. RESULTS: F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation. CONCLUSIONS: F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.

Correction: Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

The fortieth author's name was listed incorrectly. The correct presentation is A Keski-Rahkonen.

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence.

Cigarette smoking is a leading cause of preventable mortality worldwide. Nicotine dependence, which reduces the likelihood of quitting smoking, is a heritable trait with firmly established associations with sequence variants in nicotine acetylcholine receptor genes and at other loci. To search for additional loci, we conducted a genome-wide association study (GWAS) meta-analysis of nicotine dependence, totaling 38,602 smokers (28,677 Europeans/European Americans and 9925 African Americans) across 15 studies. In this largest-ever GWAS meta-analysis for nicotine dependence and the largest-ever cross-ancestry GWAS meta-analysis for any smoking phenotype, we reconfirmed the well-known CHRNA5-CHRNA3-CHRNB4 genes and further yielded a novel association in the DNA methyltransferase gene DNMT3B. The intronic DNMT3B rs910083-C allele (frequency=44-77%) was associated with increased risk of nicotine dependence at P=3.7 × 10-8 (odds ratio (OR)=1.06 and 95% confidence interval (CI)=1.04-1.07 for severe vs mild dependence). The association was independently confirmed in the UK Biobank (N=48,931) using heavy vs never smoking as a proxy phenotype (P=3.6 × 10-4, OR=1.05, and 95% CI=1.02-1.08). Rs910083-C is also associated with increased risk of squamous cell lung carcinoma in the International Lung Cancer Consortium (N=60,586, meta-analysis P=0.0095, OR=1.05, and 95% CI=1.01-1.09). Moreover, rs910083-C was implicated as a cis-methylation quantitative trait locus (QTL) variant associated with higher DNMT3B methylation in fetal brain (N=166, P=2.3 × 10-26) and a cis-expression QTL variant associated with higher DNMT3B expression in adult cerebellum from the Genotype-Tissue Expression project (N=103, P=3.0 × 10-6) and the independent Brain eQTL Almanac (N=134, P=0.028). This novel DNMT3B cis-acting QTL variant highlights the importance of genetically influenced regulation in brain on the risks of nicotine dependence, heavy smoking and consequent lung cancer.

Investigation of common, low-frequency and rare genome-wide variation in anorexia nervosa.

Anorexia nervosa (AN) is a complex neuropsychiatric disorder presenting with dangerously low body weight, and a deep and persistent fear of gaining weight. To date, only one genome-wide significant locus associated with AN has been identified. We performed an exome-chip based genome-wide association studies (GWAS) in 2158 cases from nine populations of European origin and 15 485 ancestrally matched controls. Unlike previous studies, this GWAS also probed association in low-frequency and rare variants. Sixteen independent variants were taken forward for in silico and de novo replication (11 common and 5 rare). No findings reached genome-wide significance. Two notable common variants were identified: rs10791286, an intronic variant in OPCML (P=9.89 × 10-6), and rs7700147, an intergenic variant (P=2.93 × 10-5). No low-frequency variant associations were identified at genome-wide significance, although the study was well-powered to detect low-frequency variants with large effect sizes, suggesting that there may be no AN loci in this genomic search space with large effect sizes.

A within-sibling pair analysis of lifestyle behaviours and BMI z-score in the multi-centre I.Family study.

BACKGROUND AND AIMS: By investigating differences in lifestyle behaviours and BMI in sibling pairs, family-level confounding is minimized and causal inference is improved, compared to cross-sectional studies of unrelated children. Thus, we aimed to investigate within-sibling pair differences in different lifestyle behaviours and differences in BMI z-scores in children and adolescents. METHODS AND RESULTS: We examined three groups of sibling pairs 1) all same-sex sibling pairs with maximum 4 years age difference (n = 1209 pairs from 1072 families in 8 countries, mean age 10.7 years, standard deviation 2.4 years), 2) sibling pairs discordant for overweight (n = 262) and 3) twin pairs (n = 85). Usual dietary intake was estimated by 24-h recalls and time spent in light (LPA) and moderate-to-vigorous physical activity (MVPA) was measured by accelerometers. Screen time, sleep and dieting for weight loss were assessed by questionnaires. Within all 3 groups of sibling pairs, more time in MVPA was associated with lower BMI z-score. Higher energy intake was associated with higher BMI z-score within twin pairs and within all sibling pairs who were not currently dieting for weight loss. Regarding LPA, screen time or sleep duration, no or inconsistent associations were observed for the three groups of sibling pairs. CONCLUSIONS: MVPA and energy intake were associated with BMI differences within sibling and twin pairs growing up in the same home, thus independent of family-level confounding factors. Future studies should explore whether genetic variants regulating appetite or energy expenditure behaviours account for weight differences in sibling pairs.

Genetic predisposition to obesity, restrained eating and changes in body weight: a population-based prospective study.

OBJECTIVES: There is no consensus on whether cognitive control over food intake (that is, restrained eating) is helpful, merely ineffective or actually harmful in weight management. We examined the interplay between genetic risk of obesity, restrained eating and changes in body weight and size. METHODS: Participants were Finnish aged 25-74 years who attended the DIetary, Lifestyle and Genetic determinants of Obesity and Metabolic syndrome study at baseline in 2007 and follow-up in 2014. At baseline (n=5024), height, weight and waist circumference (WC) were measured in a health examination and participants self-reported their weight at age 20 years. At follow-up (n=3735), height, weight and WC were based on measured or self-reported information. We calculated 7-year change in body mass index (BMI) and WC and annual weight change from age 20 years to baseline. Three-Factor Eating Questionnaire-R18 was used to assess restrained eating. Genetic risk of obesity was assessed by calculating a polygenic risk score of 97 known BMI-related loci. RESULTS: Cross-lagged autoregressive models indicated that baseline restrained eating was unrelated to 7-year change in BMI (ß=0.00; 95% confidence interval (CI)=-0.01, 0.02). Instead, higher baseline BMI predicted greater 7-year increases in restrained eating (ß=0.08; 95% CI=0.05, 0.11). Similar results were obtained with WC. Polygenic risk score correlated positively with restrained eating and obesity indicators in both study phases, but it did not predict 7-year change in BMI or WC. However, individuals with higher genetic risk of obesity tended to gain more weight from age 20 years to baseline, and this association was more pronounced in unrestrained eaters than in restrained eaters (P=0.038 for interaction). CONCLUSIONS: Our results suggest that restrained eating is a marker for previous weight gain rather than a factor that leads to future weight gain in middle-aged adults. Genetic influences on weight gain from early to middle adulthood may vary according to restrained eating, but this finding needs to be replicated in future studies.

Subcutaneous adipose tissue gene expression and DNA methylation respond to both short- and long-term weight loss.

BACKGROUND: Few studies have examined both gene expression and DNA methylation profiles in subcutaneous adipose tissue (SAT) during long-term weight loss. Thus, molecular mechanisms in weight loss and regain remain elusive. PARTICIPANTS/METHODS: We performed a 1-year weight loss intervention on 19 healthy obese participants (mean body mass index (BMI) 34.6 kg m-2) and studied longitudinal gene expression (Affymetrix Human Genome U133 Plus 2.0) and DNA methylation (Infinium HumanMethylation450 BeadChip) in SAT at 0, 5 and 12 months. To examine whether weight loss and acquired obesity produce reciprocal profiles, we verified our findings in 26 BMI-discordant monozygotic twin pairs. RESULTS: We found altered expression of 69 genes from 0 to 5' months (short-term) weight loss. Sixty of these genes showed reversed expression in acquired obesity (twins). Altogether 21/69 genes showed significant expression-DNA methylation correlations. Pathway analyses revealed increased high-density lipoprotein-mediated lipid transport characteristic to short-term weight loss. After the fifth month, two groups of participants evolved: weight losers (WLs) and weight regainers (WRs). In WLs five genes were differentially expressed in 5 vs 12 months, three of which significantly correlated with methylation. Signaling by insulin receptor pathway showed increased expression. We further identified 35 genes with differential expression in WLs from 0 to 12 months (long-term) weight loss, with 20 showing opposite expression patterns in acquired obesity, and 16/35 genes with significant expression-DNA methylation correlations. Pathway analyses demonstrated changes in signal transduction, metabolism, immune system and cell cycle. Notably, seven genes (UCHL1, BAG3, TNMD, LEP, BHMT2, EPDR1 and OSTM1) were found to be downregulated during both short- and long-term weight loss. CONCLUSIONS: Our study indicates short- and long-term weight loss influences in transcription and DNA methylation in SAT of healthy participants. Moreover, we demonstrate that same genes react in an opposite manner in weight loss and acquired obesity.

Physical activity, cardiorespiratory fitness, and metabolic outcomes in monozygotic twin pairs discordant for body mass index.

This study aims to investigate (i) how monozygotic (MZ) twin pairs who are discordant for body mass index (BMI) differ for objectively and subjectively measured physical activity (PA) and cardiorespiratory fitness (VO2 max) and (ii) associations of PA and VO2 max with adiposity and measures of metabolic health, in individual twins and independent of genetic and shared environmental effects within twin pairs. We examined 27 BMI-discordant and 14 BMI-concordant MZ twin pairs. Fat and fat-free mass (ffm) were measured by dual-energy X-ray absorptiometry and VO2 max by spiroergometry. PA was measured objectively by accelerometers using ActiGraph GT1M for daytime activity and Actiwatch AW7 for 24 h/d. Self-reported PA was obtained through the Baecke and IPAQ long-form questionnaires. Objectively measured moderate-to-vigorous PA (MVPA, min/d), steps/d, and VO2 max/kg were significantly lower, by 30%, 21%, and 14%, respectively, in the heavier compared with the leaner co-twins of the BMI-discordant twin pairs. There were no significant differences in self-reported PA or VO2 max/ffm. As expected, PA and VO2 max/ffm were similar in the BMI-concordant co-twins. Furthermore, the 24-h recording of activity suggested that the heavier co-twins had more restless sleep during the night, whereas the leaner co-twins were more active during the day. Within all twin pairs, higher MVPA and steps per day were associated with lower fat percentage and improved metabolic health measures. Objectively, but not subjectively measured PA is associated with lower fat percentage and better metabolic health, independent of genetic and shared environmental factors.

Gene expression profile of subcutaneous adipose tissue in BMI-discordant monozygotic twin pairs unravels molecular and clinical changes associated with sub-types of obesity.

BACKGROUND: Subcutaneous adipose tissue (SAT) undergoes major changes in obesity, but little is known about the whole-genome scale patterns of these changes or about their variation between different obesity sub-groups. We sought to compare how transcriptomics profiles in SAT differ between monozygotic (MZ) co-twins who are discordant for body mass index (BMI), whether the profiles vary between twin pairs and whether the variation can be linked to clinical characteristics. METHODS: We analysed the transcriptomics (Affymetrix U133 Plus 2.0) patterns of SAT in young MZ twin pairs (n=26, intra-pair difference in BMI >3 kg m-2, aged 23-36), from 10 birth cohorts of adult Finnish twins. The clinical data included measurements of body composition, insulin resistance, lipids and adipokines. RESULTS: We found 2108 genes differentially expressed (false discovery rate (FDR)<0.05) in SAT of the BMI-discordant pairs. Pathway analyses of these genes revealed a significant downregulation of mitochondrial oxidative pathways (P<0.05) and upregulation of inflammation pathways (P<0.05). Hierarchical clustering of heavy/lean twin ratios, representing effects of acquired obesity in the transcriptomics data, revealed three sub-groups with different molecular profiles (FDR<0.05). Analyses comparing these sub-groups showed that, in the heavy co-twins, downregulation of the mitochondrial pathways, especially that of branched chain amino acid degradation was more evident in two clusters while and upregulation of the inflammatory response was most evident in the last, presumably the unhealthiest cluster. High-fasting insulin levels and large adipocyte diameter were the predominant clinical characteristic of the heavy co-twins in this cluster (Bonferroni-adjusted P<0.05). CONCLUSIONS: This is the first study in BMI-discordant MZ twin pairs reporting sub-types of obesity based on both SAT gene expression profiles and clinical traits. We conclude that a decrease in mitochondrial BCAA degradation and an increase in inflammation in SAT co-occur and associate with hyperinsulinemia and large adipocyte size in unhealthy obesity.

Prospective association between tobacco smoking and death by suicide: a competing risks hazard analysis in a large twin cohort with 35-year follow-up.

BACKGROUND: The relationship between smoking and suicide remains controversial. METHOD: A total of 16 282 twin pairs born before 1958 in Finland and alive in 1974 were queried with detailed health and smoking questionnaires in 1975 and 1981, with response rates of 89% and 84%. Smoking status and dose, marital, employment, and socio-economic status, and indicators of psychiatric and somatic illness were assessed at both time points. Emergent psychiatric and medical illness and vital status, including suicide determined by forensic autopsy, were evaluated over 35-year follow-up through government registries. The association between smoking and suicide was determined in competing risks hazard models. In twin pairs discordant for smoking and suicide, the prospective association between smoking and suicide was determined using a matched case-control design. RESULTS: Smokers had a higher cumulative suicide incidence than former or never smokers. Heavy smokers had significantly higher suicide risk [hazard ratio (HR) 3.47, 95% confidence interval (CI) 2.31-5.22] than light smokers (HR 2.30, 95% CI 1.61-3.23) (p = 0.017). Compared with never smokers, smokers, but not former smokers, had increased suicide risk (HR 2.56, 95% CI 1.43-4.59), adjusting for depressive symptoms, alcohol and sedative-hypnotic use, and excluding those who developed serious somatic or psychiatric illness. In twin pairs discordant for smoking and suicide, suicide was more likely in smokers [odds ratio (OR) 6.0, 95% CI 2.06-23.8]. CONCLUSIONS: Adults who smoked tobacco were more likely to die by suicide, with a large, dose-dependent effect. This effect remained after consideration of many known predictors of suicide and shared familial effects, consistent with the hypothesis that exposure to tobacco smoke increases the risk of suicide.

Gene-environment interplay in depressive symptoms: moderation by age, sex, and physical illness.

BACKGROUND: Numerous factors influence late-life depressive symptoms in adults, many not thoroughly characterized. We addressed whether genetic and environmental influences on depressive symptoms differed by age, sex, and physical illness. METHOD: The analysis sample included 24 436 twins aged 40-90 years drawn from the Interplay of Genes and Environment across Multiple Studies (IGEMS) Consortium. Biometric analyses tested age, sex, and physical illness moderation of genetic and environmental variance in depressive symptoms. RESULTS: Women reported greater depressive symptoms than men. After age 60, there was an accelerating increase in depressive symptom scores with age, but this did not appreciably affect genetic and environmental variances. Overlap in genetic influences between physical illness and depressive symptoms was greater in men than in women. Additionally, in men extent of overlap was greater with worse physical illness (the genetic correlation ranged from near 0.00 for the least physical illness to nearly 0.60 with physical illness 2 s.d. above the mean). For men and women, the same environmental factors that influenced depressive symptoms also influenced physical illness. CONCLUSIONS: Findings suggested that genetic factors play a larger part in the association between depressive symptoms and physical illness for men than for women. For both sexes, across all ages, physical illness may similarly trigger social and health limitations that contribute to depressive symptoms.

Diversity of leisure-time sport activities in adolescence as a predictor of leisure-time physical activity in adulthood.

Because sustained physical activity is important for a healthy life, this paper examined whether a greater diversity of sport activities during adolescence predicts higher levels of leisure-time physical activity (LTPA) in adulthood. From sport activity participation reported by 17-year-old twins, we formed five groups: 1, 2, 3, 4, and 5+ different sport activities. At follow-up in their mid-thirties, twins were divided into four activity classes based on LTPA, including active commuting. Multinomial regression analyses, adjusted for several confounders, were conducted separately for male (N=1288) and female (N=1770) participants. Further, conditional logistic regression analysis included 23 twin pairs discordant for both diversity of sport activities in adolescence and LTPA in adulthood. The diversity of leisure-time sport activities in adolescence had a significant positive association with adulthood LTPA among females. Membership in the most active adult quartile, compared to the least active quartile, was predicted by participation in 2, 3, 4, and 5+ sport activities in adolescence with odds ratios: 1.52 (P=.11), 1.86 (P=.02), 1.29 (P=.39), and 3.12 (P=5.4e-05), respectively. Within-pair analyses, limited by the small sample of twins discordant for both adolescent activities and adult outcomes, did not replicate the association. A greater diversity of leisure-time sport activities in adolescence predicts higher levels of LTPA in adulthood in females, but the causal nature of this association remains unresolved.

Genetic architecture of motives for leisure-time physical activity: a twin study.

The aim of this study was to estimate the contribution of genetic and environmental influences on motives for engaging in leisure-time physical activity. The participants were obtained from the FinnTwin16 study. A modified version of the Recreational Exercise Motivation Measure was used to assess the motives for leisure-time physical activity in 2542 twin individuals (mean age of 34.1 years). Linear structural equation modeling was used to investigate the genetic and environmental influences on motive dimensions. The highest heritability estimates were found for the motive dimensions of "enjoyment" [men 33% (95% CI 23-43%), women 53% (95% CI 45-60%)] and "affiliation" [men 39% (95% CI 0.28-0.49%), women 35% (95% CI 0.25-0.43%)]. The lowest heritability estimates were found for others' expectations [men 13% (95% CI 0.04-0.25%), women 15% (95% CI 0.07-0.24%)]. Unique environmental influences explained the remaining variances, which ranged from 47% to 87%. The heritability estimates for summary variables of intrinsic and extrinsic motives were 36% and 32% for men and 40% and 24% for women, respectively. In conclusion, genetic factors contribute to motives for leisure-time physical activity. However, the genetic effects are, at most, moderate, implying the greater relative role of environmental factors.

The effects of parental education on exercise behavior in childhood and youth: a study in Dutch and Finnish twins.

Twin studies have estimated the relative contribution of genes and the environment to variance in exercise behavior and it is known that parental education positively affects exercise levels. This study investigates the role of parental education as a potential modifier of variance in exercise behavior from age 7 to 18 years. The study is based on large datasets from the Netherlands Twin Register (NTR: N = 24 874 twins; surveys around the ages of 7, 10, 12, 14, 16 and 18 years) and two Finnish twin cohorts (FinnTwin12: N = 4399; 12, 14 and 17 years; FinnTwin16: N = 4648; 16, 17 and 18 years). Regular participation in moderate-to-vigorous exercise activities during leisure time was assessed by survey. Parental education was dichotomized ("both parents with a low education" vs "at least one parent with a high education"). The mean in exercise behavior tended to be higher and the variance tended to be lower in children of high educated parents. Evidence for gene-by-environment interaction was weak. To develop successful interventions that specifically target children of low educated parents, the mechanisms causing the mean and variance differences between the two groups should be better understood.

Mobility and muscle strength in male former elite endurance and power athletes aged 66-91 years.

The aim of this cross-sectional study was to compare mobility and muscle strength in male former elite endurance and power athletes aged 66-91 years (n = 150; 50 men in both former elite athlete groups and in their control group). Agility, dynamic balance, walking speed, chair stand, self-rated balance confidence (ABC-scale), jumping height, and handgrip strength were assessed. Former elite power athletes had better agility performance time than the controls (age- and body mass index, BMI-adjusted mean difference -3.6 s; 95% CI -6.3, -0.8). Adjustment for current leisure time physical activity (LTPA) and prevalence of diseases made this difference non-significant (P = 0.214). The subjects in the power sports group jumped higher than the men in the control group (age- and BMI-adjusted mean differences for vertical squat jump, VSJ 4.4 cm; 95% CI 2.0, 6.8; for countermovement jump, CMJ 4.0 cm; 95% CI 1.7, 6.4). Taking current LTPA and chronic diseases for adjusting process did not improve explorative power of the model. No significant differences between the groups were found in the performances evaluating dynamic balance, walking speed, chair stand, ABC-scale, or handgrip strength. In conclusion, power athletes among the aged former elite sportsmen had greater explosive force production in their lower extremities than the men in the control group.

Biotin-dependent functions in adiposity: a study of monozygotic twin pairs.

BACKGROUND: Biotin acts as a coenzyme for carboxylases regulating lipid and amino-acid metabolism. We investigated alterations of the biotin-dependent functions in obesity and the downstream effects of biotin restriction in adipocytes in vitro. SUBJECTS: Twenty-four monozygotic twin pairs discordant for body mass index (BMI). Mean within-pair difference (heavy-lean co-twin, Δ) of BMI was 6.0 kg m(-2) (range 3.1-15.2 kg m(-)(2)). METHODS: Adipose tissue (AT) DNA methylation, gene expression of AT and adipocytes, and leukocytes (real-time quantitative PCR), serum biotin, C-reactive protein (CRP) and triglycerides were measured in the twins. Human adipocytes were cultured in low and control biotin concentrations and analyzed for lipid droplet content, mitochondrial morphology and mitochondrial respiration. RESULTS: The gene expression levels of carboxylases, PCCB and MCCC1, were upregulated in the heavier co-twins' leukocytes. ΔPCCB (r=0.91, P=0.0046) and ΔMCCC1 (r=0.79, P=0.036) correlated with ΔCRP within-pairs. Serum biotin levels were lower in the heavier (274 ng l(-1)) than in the lean co-twins (390 ng l(-1), P=0.034). ΔBiotin correlated negatively with Δtriglycerides (r=-0.56, P=0.045) within-pairs. In AT, HLCS and ACACB were hypermethylated and biotin cycle genes HLCS and BTD were downregulated (P<0.05). Biotin-dependent carboxylases were downregulated (ACACA, ACACB, PCCB, MCCC2 and PC; P<0.05) in both AT and adipocytes of the heavier co-twins. Adipocytes cultured in low biotin had decreased lipid accumulation, altered mitochondrial morphology and deficient mitochondrial respiration. CONCLUSIONS: Biotin-dependent functions are modified by adiposity independent of genetic effects, and correlate with inflammation and hypertriglyceridemia. Biotin restriction decreases lipid accumulation and respiration, and alters mitochondrial morphology in adipocytes.

DNA methylation and gene expression patterns in adipose tissue differ significantly within young adult monozygotic BMI-discordant twin pairs.

BACKGROUND: Little is known about epigenetic alterations associated with subcutaneous adipose tissue (SAT) in obesity. Our aim was to study genome-wide DNA methylation and gene expression differences in SAT in monozygotic (MZ) twin pairs who are discordant for body mass index (BMI). This design completely matches lean and obese groups for genetic background, age, gender and shared environment. METHODS: 14We analyzed DNA methylome and gene expression from SAT, together with body composition (magnetic resonance imaging/spectroscopy) and glucose tolerance test, lipids and C-reactive protein from 26 rare BMI-discordant (intrapair difference in BMI ⩾3 kg m(-2)) MZ twin pairs identified from 10 birth cohorts of young adult Finnish twins. RESULTS: We found 17 novel obesity-associated genes that were differentially methylated across the genome between heavy and lean co-twins. Nine of them were also differentially expressed. Pathway analyses indicated that dysregulation of SAT in obesity includes a paradoxical downregulation of lipo/adipogenesis and upregulation of inflammation and extracellular matrix remodeling. Furthermore, CpG sites whose methylation correlated with metabolically harmful fat depots (intra-abdominal and liver fat) also correlated with measures of insulin resistance, dyslipidemia and low-grade inflammation, thus suggesting that epigenetic alterations in SAT are associated with the development of unhealthy obesity. CONCLUSION: This is the first study in BMI-discordant MZ twin pairs reporting genome-wide DNA methylation and expression profiles in SAT. We found a number of novel genes and pathways whose methylation and expression patterns differ within the twin pairs, suggesting that the pathological adaptation of SAT to obesity is, at least in part, epigenetically regulated.

Voxel-based morphometry study on monozygotic twins discordant for Alzheimer's disease.

OBJECTIVES: We set to investigate the possible role of genes and environment in developing Alzheimer's disease (AD) in monozygotic twin pairs discordant for AD. METHODS: Three pairs of twins discordant for AD, who were enrolled in the Finnish Twin Cohort, were used in the study and compared with 13 controls. Gray matter changes were assessed with magnetic resonance images using voxel-based morphometry with statistical parametric mapping. RESULTS: In the affected twins, the peaks of volume loss were located bilaterally in the temporal (including the hippocampus), the frontal, and the parietal lobes, while in the unaffected siblings, the peaks were located in the frontal gyri and in the parietal lobule. Thus, in the unaffected twins, the pattern of volume loss overlaps with the neocortical but not with the medial temporal areas. DISCUSSION: These findings suggest that genetic factors more largely control neocortical regions, whereas environmental factors more strongly affect medial temporal regions.

Former male elite athletes have better metabolic health in late life than their controls.

Elite-class athletes have longer life expectancy and lower risk for chronic noncommunicable diseases possibly because of physically active and healthier lifestyle. In this study, we assessed former male Finnish elite-class athletes' (n = 392) and their matched controls' (n = 207) body composition, and risk for the metabolic syndrome (MS) and nonalcoholic fatty liver disease (NAFLD) in later life. Compared with the controls, the former athletes had lower body fat percentage (24.8% vs 26.0%, P = 0.021), lower risk for MS [odds ratio (OR) 0.57, 95% confidence interval (CI) 0.40-0.81], and NAFLD (OR 0.61, 95% CI 0.42-0.88). High volume of current leisure-time physical activity (LTPA) was associated with lower body fat percentage (P for trend < 0.001). When current volume of LTPA increased 1 MET h/week, the risk of MS and NAFLD decreased (OR 0.99, 95% CI 0.98-0.99 and OR 0.97, 95% CI 0.96-0.98, respectively). Although a career as an elite-class athlete during young adulthood may help to protect from developing metabolic syndrome, present exercise levels and volume of LTPA seem equally important as well.

Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample.

Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.