Increased risk of dementia differs across cardiovascular diseases and types of dementia - Data from a nationwide study.

AIMS: Dementia is a major health problem. Cardiovascular diseases (CVD) and risk factors are associated with incident dementia. However, whether there is an association among CVD, Alzheimer's disease (AD) and vascular dementia (VD) at the population level remains unclear. METHODS: We analysed the association between CVD (heart failure [HF], atrial fibrillation [AF], myocardial infarction [MI], peripheral arterial disease, stroke and transient ischemic attack) and the incidence of dementia using nationwide FinnGen data of 218,192 individuals. The last follow-up information on dementia was available from October 2021. RESULTS: The age at the end of the follow-up was 61.7 ± 17.1 years, and 53% were women. Overall, we observed 9701 (4.4%) dementia, 6323 (2.9%) AD and 1918 (0.7%) VD cases. Individuals with CVD had a higher risk of developing dementia than unexposed individuals. In the multivariable-adjusted Cox models, stroke was most strongly associated with dementia (hazard ratio [HR] 1.7, 95% confidence interval [CI] 1.6-1.8). CVD was more strongly associated with VD than with AD. Individuals with HF and MI had an increased risk of AD (HF: HR 1.11, 95% CI 1.04-1.19; MI: HR 1.10, 95% CI 1.02-1.18). AF was associated with VD (HR 1.58, 95% CI 1.42-1.77), but not with AD (HR 1.03, 95% CI 0.97-1.09). Clinical characteristics, such as diabetes, smoking and alcohol abuse, were associated with both types of dementia. CONCLUSION: All major CVDs were associated with an increased risk of developing dementia, particularly VD. Therefore, CVD onset should prompt an assessment of cognitive decline and possible preventive measures.

Gut microbiome and atrial fibrillation-results from a large population-based study.

BACKGROUND: Atrial fibrillation (AF) is an important heart rhythm disorder in aging populations. The gut microbiome composition has been previously related to cardiovascular disease risk factors. Whether the gut microbial profile is also associated with the risk of AF remains unknown. METHODS: We examined the associations of prevalent and incident AF with gut microbiota in the FINRISK 2002 study, a random population sample of 6763 individuals. We replicated our findings in an independent case-control cohort of 138 individuals in Hamburg, Germany. FINDINGS: Multivariable-adjusted regression models revealed that prevalent AF (N = 116) was associated with nine microbial genera. Incident AF (N = 539) over a median follow-up of 15 years was associated with eight microbial genera with false discovery rate (FDR)-corrected P < 0.05. Both prevalent and incident AF were associated with the genera Enorma and Bifidobacterium (FDR-corrected P < 0.001). AF was not significantly associated with bacterial diversity measures. Seventy-five percent of top genera (Enorma, Paraprevotella, Odoribacter, Collinsella, Barnesiella, Alistipes) in Cox regression analyses showed a consistent direction of shifted abundance in an independent AF case-control cohort that was used for replication. INTERPRETATION: Our findings establish the basis for the use of microbiome profiles in AF risk prediction. However, extensive research is still warranted before microbiome sequencing can be used for prevention and targeted treatment of AF. FUNDING: This study was funded by European Research Council, German Ministry of Research and Education, Academy of Finland, Finnish Medical Foundation, and the Finnish Foundation for Cardiovascular Research, the Emil Aaltonen Foundation, and the Paavo Nurmi Foundation.

Inflammatory proteomics profiling for prediction of incident atrial fibrillation.

OBJECTIVE: Atrial fibrillation (AF) has emerged as a common condition in older adults. Cardiovascular risk factors only explain about 50% of AF cases. Inflammatory biomarkers may help close this gap as inflammation can alter atrial electrophysiology and structure. This study aimed to determine a cytokine biomarker profile for this condition in the community using a proteomics approach. METHODS: This study uses cytokine proteomics in participants of the Finnish population-based FINRISK cohort studies 1997/2002. Risk models for 46 cytokines were developed to predict incident AF using Cox regressions. Furthermore, the association of participants' C reactive protein (CRP) and N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations with incident AF was examined. RESULTS: In 10 744 participants (mean age of 50.9 years, 51.3% women), 1246 cases of incident AF were observed (40.5% women). The main analyses, adjusted for participants' sex and age, suggested that higher concentrations of macrophage inflammatory protein-1ß (HR=1.11; 95% CI 1.04, 1.17), hepatocyte growth factor (HR=1.12; 95% CI 1.05, 1.19), CRP (HR=1.17; 95% CI 1.10, 1.24) and NT-proBNP (HR=1.58; 95% CI 1.45, 1.71) were associated with increased risk of incident AF. In further clinical variable-adjusted models, only NT-proBNP remained statistically significant. CONCLUSION: Our study confirmed NT-proBNP as a strong predictor for AF. Observed associations of circulating inflammatory cytokines were primarily explained by clinical risk factors and did not improve risk prediction. The potential mechanistic role of inflammatory cytokines measured in a proteomics approach remains to be further elucidated.

Variants in regulatory elements of PDE4D associate with major mental illness in the Finnish population.

We have previously reported a replicable association between variants at the PDE4D gene and familial schizophrenia in a Finnish cohort. In order to identify the potential functional mutations underlying these previous findings, we sequenced 1.5 Mb of the PDE4D genomic locus in 20 families (consisting of 96 individuals and 79 independent chromosomes), followed by two stages of genotyping across 6668 individuals from multiple Finnish cohorts for major mental illnesses. We identified 4570 SNPs across the PDE4D gene, with 380 associated to schizophrenia (p ≤ 0.05). Importantly, two of these variants, rs35278 and rs165940, are located at transcription factor-binding sites, and displayed replicable association in the two-stage enlargement of the familial schizophrenia cohort (combined statistics for rs35278 p = 0.0012; OR = 1.18, 95% CI: 1.06-1.32; and rs165940 p = 0.0016; OR = 1.27, 95% CI: 1.13-1.41). Further analysis using additional cohorts and endophenotypes revealed that rs165940 principally associates within the psychosis (p = 0.025, OR = 1.18, 95% CI: 1.07-1.30) and cognitive domains of major mental illnesses (g-score p = 0.044, ß = -0.033). Specifically, the cognitive domains represented verbal learning and memory (p = 0.0091, ß = -0.044) and verbal working memory (p = 0.0062, ß = -0.036). Moreover, expression data from the GTEx database demonstrated that rs165940 significantly correlates with the mRNA expression levels of PDE4D in the cerebellum (p-value = 0.04; m-value = 0.9), demonstrating a potential functional consequence for this variant. Thus, rs165940 represents the most likely functional variant for major mental illness at the PDE4D locus in the Finnish population, increasing risk broadly to psychotic disorders.

Anodal tDCS Over the Left Prefrontal Cortex Does Not Cause Clinically Significant Changes in Circulating Metabolites.

BACKGROUND: Transcranial direct current stimulation (tDCS), a putative treatment for depression, has been proposed to affect peripheral metabolism. Metabolic products from brain tissue may also cross the blood-brain barrier, reflecting the conditions in the brain. However, there are no previous data regarding the effect of tDCS on circulating metabolites. OBJECTIVE: To determine whether five daily sessions of tDCS modulate peripheral metabolites in healthy adult men. METHODS: This double-blind, randomized controlled trial involved 79 healthy males (aged 20-40 years) divided into two groups, one receiving tDCS (2 mA) and the other sham stimulated. The anode was placed over the left dorsolateral prefrontal cortex and the cathode over the corresponding contralateral area. Venous blood samples were obtained before and after the first stimulation session, and after the fifth stimulation session. Serum levels of 102 metabolites were determined by mass spectrometry. The results were analysed with generalised estimating equations corrected for the family-wise error rate. In addition, we performed power calculations estimating sample sizes necessary for future research. RESULTS: TDCS-related variation in serum metabolite levels was extremely small and statistically non-significant. Power calculations indicated that for the observed variation to be deemed significant, samples sizes of up to 11,000 subjects per group would be required, depending on the metabolite of interest. CONCLUSION: Our study found that five sessions of tDCS induced no major effects on peripheral metabolites among healthy men. These observations support the view of tDCS as a safe treatment that does not induce significant changes in the measured peripheral metabolites in healthy male subjects.

The NDE1 genomic locus can affect treatment of psychiatric illness through gene expression changes related to microRNA-484.

Genetic studies of familial schizophrenia in Finland have observed significant associations with a group of biologically related genes, DISC1, NDE1, NDEL1, PDE4B and PDE4D, the 'DISC1 network'. Here, we use gene expression and psychoactive medication use data to study their biological consequences and potential treatment implications. Gene expression levels were determined in 64 individuals from 18 families, while prescription medication information has been collected over a 10-year period for 931 affected individuals. We demonstrate that the NDE1 SNP rs2242549 associates with significant changes in gene expression for 2908 probes (2542 genes), of which 794 probes (719 genes) were replicable. A significant number of the genes altered were predicted targets of microRNA-484 (p = 3.0 × 10-8), located on a non-coding exon of NDE1 Variants within the NDE1 locus also displayed significant genotype by gender interaction to early cessation of psychoactive medications metabolized by CYP2C19. Furthermore, we demonstrate that miR-484 can affect the expression of CYP2C19 in a cell culture system. Thus, variation at the NDE1 locus may alter risk of mental illness, in part through modification of miR-484, and such modification alters treatment response to specific psychoactive medications, leading to the potential for use of this locus in targeting treatment.

Genome-Wide Association Study of Psychosis Proneness in the Finnish Population.

The current study examined quantitative measures of psychosis proneness in a nonpsychotic population, in order to elucidate their underlying genetic architecture and to observe if there is any commonality to that already detected in the studies of individuals with overt psychotic conditions, such as schizophrenia and bipolar disorder. Heritability, univariate and multivariate genome-wide association (GWAs) tests, including a series of comprehensive gene-based association analyses, were developed in 4269 nonpsychotic persons participating in the Northern Finland Birth Cohort 1966 study with information on the following psychometric measures: Hypomanic Personality, Perceptual Aberration, Physical and Social Anhedonia (also known as Chapman's Schizotypia scales), and Schizoidia scale. Genome-wide genetic data was available for ~9.84 million SNPs. Heritability estimates ranged from 16% to 27%. Phenotypic, genetic and environmental correlations ranged from 0.04-0.43, 0.25-0.73, and 0.12-0.43, respectively. Univariate GWAs tests revealed an intronic SNP (rs12449097) at the TMC7 gene (16p12.3) that significantly associated (P = 3.485 × 10-8) with the hypomanic scale. Bivariate GWAs tests including the hypomanic and physical anhedonia scales suggested a further borderline significant SNP (rs188320715; P-value = 5.261 × 10-8, ~572 kb downstream the ARID1B gene at 6q25.3). Gene-based tests highlighted 20 additional genes of which 5 had previously been associated to schizophrenia and/or bipolar disorder: CSMD1, CCDC141, SLC1A2, CACNA1C, and SNAP25. Altogether the findings explained from 3.7% to 14.1% of the corresponding trait heritability. In conclusion, this study provides preliminary genomic evidence suggesting that qualitatively similar biological factors may underlie different psychosis proneness measures, some of which could further predispose to schizophrenia and bipolar disorder.

Maternal Licorice Consumption During Pregnancy and Pubertal, Cognitive, and Psychiatric Outcomes in Children.

Earlier puberty, especially in girls, is associated with physical and mental disorders. Prenatal glucocorticoid exposure influences the timing of puberty in animal models, but the human relevance of those findings is unknown. We studied whether voluntary consumption of licorice, which contains glycyrrhizin (a potent inhibitor of placental 11ß-hydroxysteroid dehydrogenase type 2, the "barrier" to maternal glucocorticoids), by pregnant women was associated with pubertal maturation (height, weight, body mass index for age, difference between current and expected adult height, Tanner staging, score on the Pubertal Development Scale), neuroendocrine function (diurnal salivary cortisol, dexamethasone suppression), cognition (neuropsychological tests), and psychiatric problems (as measured by the Child Behavior Checklist) in their offspring. The children were born in 1998 in Helsinki, Finland, and examined during 2009-2011 (mean age = 12.5 (standard deviation (SD), 0.4) years; n = 378). Girls exposed to high maternal glycyrrhizin consumption (≥500 mg/week) were taller (mean difference (MD) = 0.4 SD, 95% confidence interval (CI): 0.1, 0.8), were heavier (MD = 0.6 SD, 95% CI: 0.2, 1.9), and had higher body mass index for age (MD = 0.6 SD, 95% CI: 0.2, 0.9). They were also 0.5 standard deviations (95% CI: 0.2, 0.8) closer to adult height and reported more advanced pubertal development (P < 0.04). Girls and boys exposed to high maternal glycyrrhizin consumption scored 7 (95% CI: 3.1, 11.2) points lower on tests of intelligence quotient, had poorer memory (P < 0.04), and had 3.3-fold (95% CI: 1.4, 7.7) higher odds of attention deficit/hyperactivity disorder problems compared with children whose mothers consumed little to no glycyrrhizin (≤249 mg/week). No differences in cortisol levels were found. Licorice consumption during pregnancy may be associated with harm for the developing offspring.

A randomized controlled trial on the effects of combined aerobic-resistance exercise on muscle strength and fatigue, glycemic control and health-related quality of life of type 2 diabetes patients.

BACKGROUND: The aim of this paper was to evaluate the effects of a 12-weeks combined aerobic-resistance exercise therapy on fatigue and isokinetic muscle strength, glycemic control and health-related quality of life (HRQoL) in moderately affected type 2 diabetes (T2DM) patients. METHODS: A randomized controlled trial design was employed. Forty-three T2DM patients were assigned to an exercise group (N.=22), performing 3 weekly sessions of 60 minutes of combined aerobic-resistance exercise for 12-weeks; or a no exercise control group (N.=21). Both groups were evaluated at a baseline and after 12-weeks of exercise therapy for: 1) muscle strength and fatigue by isokinetic dynamometry; 2) plasma glycated hemoglobin A1C (HbA1C); and 3) HRQoL utilizing the SF-36 questionnaire. RESULTS: The exercise therapy led to improvements in muscle fatigue in knee extensors (-55%) and increased muscle strength in knee flexors and extensors (+15 to +30%), while HbA1C decreased (-18%). In addition, the exercising patients showed sizeable improvements in HRQoL: physical function (+53%), vitality (+21%) and mental health (+40%). CONCLUSIONS: Twelve-weeks of combined aerobic-resistance exercise was highly effective to improve muscle strength and fatigue, glycemic control and several aspects of HRQoL in T2DM patients. These data encourage the use of aerobic and resistance exercise in the good clinical care of T2DM.

Abdominal obesity and circulating metabolites: A twin study approach.

OBJECTIVE: To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors. SUBJECTS AND METHODS: Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (rg) and environmental (re) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs (intrapair BMI difference ≥3 kg/m(2)). RESULTS: Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (rg=0.40), glycoprotein (rg=0.37), serum triglycerides (rg=0.36), BCAAs (rg=0.30-0.40), HDL particle diameter (rg=-0.33) and HDL cholesterol (rg=-0.30). The effect of acquired obesity within the discordant MZ pairs was particularly strong for atherogenic lipoproteins. CONCLUSIONS: A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability.

Lumbar spinal stenosis is a highly genetic condition partly mediated by disc degeneration.

Objective. Lumbar spinal stenosis is one of the most commonly diagnosed spinal disorders in older adults. Although the pathophysiology of the clinical syndrome is not well understood, a narrow central canal or intervertebral foramen is an essential or defining feature. The aim of the present study was to estimate the magnitude of genetic versus environmental influences on central lumbar spinal stenosis and to investigate disc degeneration and stature or bone development as possible genetic pathways.Methods. A classic twin study with multivariate analyses considering lumbar level and other covariates was conducted. The study sample comprised 598 male twins (147 monozygotic and 152 dizygotic pairs), 35-70 years of age, from the population-based Finnish Twin Cohort. The primary phenotypes were central lumbar stenosis as assessed qualitatively on magnetic resonance imaging (MRI) and quantitatively measured dural sac cross-sectional area. Additional phenotypes (to examine possible genetic pathways) included disc bulging and standing height, as an indicator of overall skeletal size or development.Results. The heritability estimate (h²) for qualitatively assessed central lumbar spinal stenosis on MRI was 66.9% (95% confidence interval [95% CI] 56.8,74.5). The broad-sense heritability estimate for dural sac cross-sectional area was 81.2% (95% CI 74.5, 86.1),with a similar magnitude of genetic influences across lumbar levels (h²=72.4­75.6). The additive genetic correlation of quantitatively assessed stenosis and disc bulging was extremely high. There was no indication of shared genetic influences between stenosis and stature.Conclusion. Central lumbar spinal stenosis and associated dural sac dimensions are highly genetic, and disc degeneration (bulging) appears to be one pathway through which genes influence spinal stenosis.

Neuropeptide precursor VGF is genetically associated with social anhedonia and underrepresented in the brain of major mental illness: its downregulation by DISC1.

In a large Scottish pedigree, disruption of the gene coding for DISC1 clearly segregates with major depression, schizophrenia and related mental conditions. Thus, study of DISC1 may provide a clue to understand the biology of major mental illness. A neuropeptide precursor VGF has potent antidepressant effects and has been reportedly associated with bipolar disorder. Here we show that DISC1 knockdown leads to a reduction of VGF, in neurons. VGF is also downregulated in the cortices from sporadic cases with major mental disease. A positive correlation of VGF single-nucleotide polymorphisms (SNPs) with social anhedonia was also observed. We now propose that VGF participates in a common pathophysiology of major mental disease.

Utilizing twins as controls for non-twin case-materials in genome wide association studies.

Twin registries around the globe have collected DNA samples from large numbers of monozygotic and dizygotic twins. The twin sample collections are frequently used as controls in disease-specific studies together with non-twins. This approach is unbiased under the hypothesis that twins and singletons are comparable in terms of allele frequencies; i.e. there are no genetic variants associated with being a twin per se. To test this hypothesis we performed a genome-wide association study comparing the allele frequency of 572,352 single nucleotide polymorphisms (SNPs) in 1,413 monozygotic (MZ) and 5,451 dizygotic (DZ) twins with 3,720 healthy singletons. Twins and singletons have been genotyped using the same platform. SNPs showing association with being a twin at P-value < 1 × 10(-5) were selected for replication analysis in 1,492 twins (463 MZ and 1,029 DZ) and 1,880 singletons from Finland. No SNPs reached genome-wide significance (P-value < 5 × 10(-8)) in the main analysis combining MZ and DZ twins. In a secondary analysis including only DZ twins two SNPs (rs2033541 close to ADAMTSL1 and rs4149283 close to ABCA1) were genome-wide significant after meta-analysis with the Finnish population. The estimated proportion of variance on the liability scale explained by all SNPs was 0.08 (P-value=0.003) when MZ and DZ were considered together and smaller for MZ (0.06, P-value=0.10) compared to DZ (0.09, P-value=0.003) when analyzed separately. In conclusion, twins and singletons can be used in genetic studies together with general population samples without introducing large bias. Further research is needed to explore genetic variances associated with DZ twinning.

Genetic and environmental influences on longitudinal changes in leisure-time physical activity from adolescence to young adulthood.

The aim of this study was to estimate genetic and environmental influences on the longitudinal evolution of leisure-time physical activity habits from adolescence to young adulthood. Data were gathered at four time points, at mean ages 16.2, 17.1, 18.6, and 24.5 years. At baseline, the sample comprised 5,216 monozygotic and dizygotic twins, born 1975-1979, and, at the last follow-up point, of 4,531 monozygotic and dizygotic twins. Physical activity volume was assessed as frequency of leisure-time physical activity and participants were categorized into three groups: inactive, moderately active, and active. Genetic and environmental influences were estimated using a multivariate, longitudinal Cholesky decomposition with a 'multifactorial liability threshold' approach. The results suggest that, in both sexes the heritability of leisure-time physical activity remained moderate (~43-52%) during adolescence, declining to ~30% in young adulthood. Shared environmental influences increased from adolescence (~18-26%) to young adulthood (43% in men and 49% in women). Specific environmental influences remained relatively stable during the total follow-up (~20-30%). New genetic, shared, and specific environmental influences at every follow-up point were suggested by the low correlations across occasions. In conclusion, the study demonstrated gender differences in genetic influences in the evolution of leisure-time physical activity habits from adolescence to young adulthood. However, shared environmental influences, especially in women, were crucial in explaining longitudinal changes in leisure-time physical activity. These outcomes emphasize the need of gender-specific measures to promote physical activity habits during young adulthood.

Genome-wide association study identifies multiple loci influencing human serum metabolite levels.

Nuclear magnetic resonance assays allow for measurement of a wide range of metabolic phenotypes. We report here the results of a GWAS on 8,330 Finnish individuals genotyped and imputed at 7.7 million SNPs for a range of 216 serum metabolic phenotypes assessed by NMR of serum samples. We identified significant associations (P < 2.31 × 10(-10)) at 31 loci, including 11 for which there have not been previous reports of associations to a metabolic trait or disorder. Analyses of Finnish twin pairs suggested that the metabolic measures reported here show higher heritability than comparable conventional metabolic phenotypes. In accordance with our expectations, SNPs at the 31 loci associated with individual metabolites account for a greater proportion of the genetic component of trait variance (up to 40%) than is typically observed for conventional serum metabolic phenotypes. The identification of such associations may provide substantial insight into cardiometabolic disorders.

Genetic and environmental factors influencing BMI development from adolescence to young adulthood.

BMI increases progressively from adolescence to young adulthood. The aims of the present study were firstly, to investigate the extent to which genetic and environmental influences account for differences in BMI trajectories during this period, and secondly to examine whether boys and girls show divergences in these influences, as their BMI normally start differing across adolescence. The study sample consisted of 4,915 monozygotic and like- and unlike-sex dizygotic twins, born between 1975 and 1979. Data on BMI was gathered when twins were on average 16.1, 17.1, 18.6 and 24.4 years old. Genetic and environmental influences on the BMI trajectories were modeled using a latent growth curve approach. The results showed that the heritability of BMI decreased slightly after the adolescence period, from ≈ 80 to 70%. BMI transition from adolescence to young adulthood was best described by a quadratic trajectory that was highly accounted (61.7-86.5%) for by additive genetic influences. Genetic influences on BMI level showed a low correlation with those on the trend in BMI with age indicating that different sets of genes underlie the change of BMI during this period. Importantly, the analyses also evidenced that different genetic and environmental influences may underlie boys and girls evolution. In conclusion, our results suggested specific genetic influences accounting for the BMI rate-of-change from adolescence to young adulthood. This indicates that the specific genes behind BMI level may not be the same as the genes affecting BMI change which should be taken into account in further efforts to identify these genes.

Genetic and environmental influences on growth from late childhood to adulthood: a longitudinal study of two Finnish twin cohorts.

OBJECTIVES: Human growth is a complex process that remains insufficiently understood. We aimed to analyze genetic and environmental influences on growth from late childhood to early adulthood. METHODS: Two cohorts of monozygotic and dizygotic (same sex and opposite sex) Finnish twin pairs were studied longitudinally using self-reported height at 11-12, 14, and 17 years and adult age (FinnTwin12) and at 16, 17, and 18 years and adult age (FinnTwin16). Univariate and multivariate variance component models for twin data were used. RESULTS: From childhood to adulthood, genetic differences explained 72-81% of the variation of height in boys and 65-86% in girls. Environmental factors common to co-twins explained 5-23% of the variation of height, with the residual variation explained by environmental factors unique to each twin individual. Common environmental factors affecting height were highly correlated between the analyzed ages (0.72-0.99 and 0.91-1.00 for boys and girls, respectively). Genetic (0.58-0.99 and 0.70-0.99, respectively) and unique environmental factors (0.32-0.78 and 0.54-0.82, respectively) affecting height at different ages were more weakly, but still substantially, correlated. CONCLUSIONS: The genetic contribution to height is strong during adolescence. The high genetic correlations detected across the ages encourage further efforts to identify genes affecting growth. Common and unique environmental factors affecting height during adolescence are also important, and further studies are necessary to identify their nature and test whether they interact with genetic factors.

Serum angiopoietin-like 4 protein levels and expression in adipose tissue are inversely correlated with obesity in monozygotic twins.

Animal studies have suggested that angiopoietin-like 4 (Angptl4) regulates adiposity through central and peripheral mechanisms. The aim of this study was to investigate whether serum concentration and adipose tissue expression of Angptl4 are associated with obesity-related parameters in humans. Altogether, 75 dizygotic (DZ) and 46 monozygotic (MZ) twin pairs were studied, from the FinnTwin12 and FinnTwin16 cohorts. Among the MZ pairs, 21 were discordant for body mass index (BMI) (intra-pair BMI-difference >2.5 kg/m², age 23-33 years). Serum Angptl4 (s-Angptl4) levels were measured by ELISA, and adipose tissue gene expression was analyzed by genome-wide transcript profiling. In MZ twin pairs discordant for BMI, s-Angptl4 and adipose tissue ANGPTL4 mRNA (at-ANGPTL4) levels were significantly decreased (P = 0.04 and P = 0.03, respectively) in obese twins as compared with their nonobese cotwins. In all twins, intra-pair differences in s-Angptl4 levels were inversely correlated with intra-pair differences in BMI (r = -0.27, P = 0.003). In individual MZ twins, at-ANGPTL4 expression was inversely correlated with BMI (r = -0.44, P = 0.001) and positively correlated with at-LIPE (r = 0.24, P = 0.01) and at-ABHD5 (r = 0.41, P = 0.005) expression. Our results demonstrated that variation in Angptl4 concentration was only modestly accounted for by genetic factors and suggest a role for Angptl4 in acquired obesity in humans.