Publications by authors named "Jaakko Kaprio"

842 Publications

The association between epigenetic clocks and physical functioning in older women: a three-year follow-up.

J Gerontol A Biol Sci Med Sci 2021 Sep 20. Epub 2021 Sep 20.

Faculty of Sport and Health Sciences, Gerontology Research Center (GEREC), University of Jyväskylä, Jyväskylä, Finland.

Background: Epigenetic clocks are composite markers developed to predict chronological age or mortality risk from DNA methylation (DNAm) data. The present study investigated the associations between four epigenetic clocks (Horvath's and Hannum's DNAmAge and DNAm GrimAge and PhenoAge) and physical functioning during a three-year follow-up.

Methods: We studied 63-76-year-old women (n = 413) from the Finnish Twin Study on Aging. DNAm was measured from blood samples at baseline. Age acceleration (AgeAccel) i.e. discrepancy between chronological age and DNAm age was determined as residuals from linear model. Physical functioning was assessed under standardized laboratory conditions at baseline and at follow-up. A cross-sectional analysis was performed with path models, and a longitudinal analysis was conducted with repeated measures linear models. A nonrandom missing data analysis was performed.

Results: In comparison to the other clocks, GrimAgeAccel was more strongly associated with physical functioning. At baseline, GrimAgeAccel was associated with lower performance in the Timed Up and Go (TUG) test and the six-minute walk test. At follow-up, significant associations were observed between GrimAgeAccel and lowered performance in the TUG, six-minute and 10-meter walk tests, and knee extension and ankle plantar flexion strength tests.

Conclusions: The DNAm GrimAge, a novel estimate of biological aging, associated with decline in physical functioning over the three-year follow-up in older women. However, associations between chronological age and physical function phenotypes followed similar pattern. Current epigenetic clocks do not provide strong benefits in predicting the decline of physical functioning at least during a rather short follow-up period and restricted age-range.
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http://dx.doi.org/10.1093/gerona/glab270DOI Listing
September 2021

Predicting Alcohol Dependence Symptoms by Young Adulthood: A Co-Twin Comparisons Study.

Twin Res Hum Genet 2021 Sep 16:1-13. Epub 2021 Sep 16.

Department of Psychology, Virginia Commonwealth University, Richmond, Virginia, USA.

Co-twin comparisons address familial confounding by controlling for genetic and environmental influences that twin siblings share. We applied the co-twin comparison design to investigate associations of adolescent factors with alcohol dependence (AD) symptoms. Participants were 1286 individuals (581 complete twin pairs; 42% monozygotic; and 54% female) from the FinnTwin12 study. Predictors included adolescent academic achievement, substance use, externalizing problems, internalizing problems, executive functioning, peer environment, physical health, relationship with parents, alcohol expectancies, life events, and pubertal development. The outcome was lifetime AD clinical criterion count, as measured in young adulthood. We examined associations of each adolescent domain with AD symptoms in individual-level and co-twin comparison analyses. In individual-level analyses, adolescents with higher levels of substance use, teacher-reported externalizing problems at age 12, externalizing problems at age 14, self- and co-twin-reported internalizing problems, peer deviance, and perceived difficulty of life events reported more symptoms of AD in young adulthood (ps < .044). Conversely, individuals with higher academic achievement, social adjustment, self-rated health, and parent-child relationship quality met fewer AD clinical criteria (ps < .024). Associations between adolescent substance use, teacher-reported externalizing problems, co-twin-reported internalizing problems, peer deviance, self-rated health, and AD symptoms were of a similar magnitude in co-twin comparisons. We replicated many well-known adolescent correlates of later alcohol problems, including academic achievement, substance use, externalizing and internalizing problems, self-rated health, and features of the peer environment and parent-child relationship. Furthermore, we demonstrate the utility of co-twin comparisons for understanding pathways to AD. Effect sizes corresponding to the associations between adolescent substance use, teacher-reported externalizing problems, co-twin-reported internalizing problems, peer deviance, and self-rated health were not significantly attenuated (p value threshold = .05) after controlling for genetic and environmental influences that twin siblings share, highlighting these factors as candidates for further research.
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http://dx.doi.org/10.1017/thg.2021.36DOI Listing
September 2021

Incidence of surgery for chronic subdural hematoma in Finland during 1997-2014: a nationwide study.

J Neurosurg 2021 Sep 10:1-8. Epub 2021 Sep 10.

1Department of Neurosurgery, University of Helsinki and Helsinki University Hospital.

Objective: The number of surgeries performed for chronic subdural hematoma (CSDH) has increased. However, these changes have been poorly reported. The authors aimed to assess the national incidence of surgeries for CSDH in Finland during an 18-year time period from 1997 to 2014. They hypothesized that the incidence of CSDH surgeries has continued to increase, particularly among the elderly.

Methods: A nationwide register-based follow-up study was performed using the Finnish Care Register for Health Care. All adult patients undergoing primary CSDH surgeries during 1997-2014 were included. The study population was followed up from the time of CSDH surgery until death or the end of follow-up on December 31, 2017. The incidences of CSDH surgery per 100,000 person-years were calculated separately in each age group and sex. Age standardization was performed for those 20 years of age and older with weights from the 2013 European Standard Population. Negative binomial regression models were used to assess changes in incidence rate ratios (IRRs) during the study period.

Results: In total, 9280 patients were identified. The age-standardized incidence of CSDH surgery increased from 12.2 to 16.5 per 100,000 person-years during 1997-2014. The age- and sex-adjusted incidence of CSDH surgery increased by 30% (IRR 1.30, 95% CI 1.20-1.41). The age- and sex-adjusted incidence increased more in the older age groups, with an IRR of 1.24 for those aged 60-69 years, 1.32 for those 70-79 years, 1.46 for those 80-89 years, and 1.85 for those aged 90 years or older. The adjusted incidence did not increase for those aged 18-59 years. The sex difference (2:1 men/women) was consistent throughout the study period, with a higher incidence among men. One year after the primary surgery, 19% of the population had a resurgery, and the 1-year case fatality rate was 15%. The median age of patients increased from 73 to 76 years.

Conclusions: During the past 2 decades, the age- and sex-adjusted incidence of CSDH surgery has increased in Finland, with major increases for those aged 60 years or older. This increase is likely to continue in parallel with the aging population and increased life expectancies.
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http://dx.doi.org/10.3171/2021.3.JNS21281DOI Listing
September 2021

Genomic and phenotypic insights from an atlas of genetic effects on DNA methylation.

Nat Genet 2021 Sep 6;53(9):1311-1321. Epub 2021 Sep 6.

Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.

Characterizing genetic influences on DNA methylation (DNAm) provides an opportunity to understand mechanisms underpinning gene regulation and disease. In the present study, we describe results of DNAm quantitative trait locus (mQTL) analyses on 32,851 participants, identifying genetic variants associated with DNAm at 420,509 DNAm sites in blood. We present a database of >270,000 independent mQTLs, of which 8.5% comprise long-range (trans) associations. Identified mQTL associations explain 15-17% of the additive genetic variance of DNAm. We show that the genetic architecture of DNAm levels is highly polygenic. Using shared genetic control between distal DNAm sites, we constructed networks, identifying 405 discrete genomic communities enriched for genomic annotations and complex traits. Shared genetic variants are associated with both DNAm levels and complex diseases, but only in a minority of cases do these associations reflect causal relationships from DNAm to trait or vice versa, indicating a more complex genotype-phenotype map than previously anticipated.
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http://dx.doi.org/10.1038/s41588-021-00923-xDOI Listing
September 2021

Educational attainment of same-sex and opposite-sex dizygotic twins: An individual-level pooled study of 19 twin cohorts.

Horm Behav 2021 Sep 3;136:105054. Epub 2021 Sep 3.

Psychology Department, University of Nevada Las Vegas, Nevada, USA.

Comparing twins from same- and opposite-sex pairs can provide information on potential sex differences in a variety of outcomes, including socioeconomic-related outcomes such as educational attainment. It has been suggested that this design can be applied to examine the putative role of intrauterine exposure to testosterone for educational attainment, but the evidence is still disputed. Thus, we established an international database of twin data from 11 countries with 88,290 individual dizygotic twins born over 100 years and tested for differences between twins from same- and opposite-sex dizygotic pairs in educational attainment. Effect sizes with 95% confidence intervals (CI) were estimated by linear regression models after adjusting for birth year and twin study cohort. In contrast to the hypothesis, no difference was found in women (β = -0.05 educational years, 95% CI -0.11, 0.02). However, men with a same-sex co-twin were slightly more educated than men having an opposite-sex co-twin (β = 0.14 educational years, 95% CI 0.07, 0.21). No consistent differences in effect sizes were found between individual twin study cohorts representing Europe, the USA, and Australia or over the cohorts born during the 20th century, during which period the sex differences in education reversed favoring women in the latest birth cohorts. Further, no interaction was found with maternal or paternal education. Our results contradict the hypothesis that there would be differences in the intrauterine testosterone levels between same-sex and opposite-sex female twins affecting education. Our findings in men may point to social dynamics within same-sex twin pairs that may benefit men in their educational careers.
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http://dx.doi.org/10.1016/j.yhbeh.2021.105054DOI Listing
September 2021

Genetic association study of childhood aggression across raters, instruments, and age.

Transl Psychiatry 2021 07 30;11(1):413. Epub 2021 Jul 30.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Childhood aggressive behavior (AGG) has a substantial heritability of around 50%. Here we present a genome-wide association meta-analysis (GWAMA) of childhood AGG, in which all phenotype measures across childhood ages from multiple assessors were included. We analyzed phenotype assessments for a total of 328 935 observations from 87 485 children aged between 1.5 and 18 years, while accounting for sample overlap. We also meta-analyzed within subsets of the data, i.e., within rater, instrument and age. SNP-heritability for the overall meta-analysis (AGG) was 3.31% (SE = 0.0038). We found no genome-wide significant SNPs for AGG. The gene-based analysis returned three significant genes: ST3GAL3 (P = 1.6E-06), PCDH7 (P = 2.0E-06), and IPO13 (P = 2.5E-06). All three genes have previously been associated with educational traits. Polygenic scores based on our GWAMA significantly predicted aggression in a holdout sample of children (variance explained = 0.44%) and in retrospectively assessed childhood aggression (variance explained = 0.20%). Genetic correlations (r) among rater-specific assessment of AGG ranged from r = 0.46 between self- and teacher-assessment to r = 0.81 between mother- and teacher-assessment. We obtained moderate-to-strong rs with selected phenotypes from multiple domains, but hardly with any of the classical biomarkers thought to be associated with AGG. Significant genetic correlations were observed with most psychiatric and psychological traits (range [Formula: see text]: 0.19-1.00), except for obsessive-compulsive disorder. Aggression had a negative genetic correlation (r = ~-0.5) with cognitive traits and age at first birth. Aggression was strongly genetically correlated with smoking phenotypes (range [Formula: see text]: 0.46-0.60). The genetic correlations between aggression and psychiatric disorders were weaker for teacher-reported AGG than for mother- and self-reported AGG. The current GWAMA of childhood aggression provides a powerful tool to interrogate the rater-specific genetic etiology of AGG.
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http://dx.doi.org/10.1038/s41398-021-01480-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324785PMC
July 2021

Familial Risk and Heritability of Hematologic Malignancies in the Nordic Twin Study of Cancer.

Cancers (Basel) 2021 Jun 16;13(12). Epub 2021 Jun 16.

Department of Epidemiology, Biostatistics, and Biodemography, Institute of Public Health, University of Southern Denmark, 5000 Odense C, Denmark.

We aimed to explore the genetic and environmental contributions to variation in the risk of hematologic malignancies and characterize familial dependence within and across hematologic malignancies. The study base included 316,397 individual twins from the Nordic Twin Study of Cancer with a median of 41 years of follow-up: 88,618 (28%) of the twins were monozygotic, and 3459 hematologic malignancies were reported. We estimated the cumulative incidence by age, familial risk, and genetic and environmental variance components of hematologic malignancies accounting for competing risk of death. The lifetime risk of any hematologic malignancy was 2.5% (95% CI 2.4-2.6%), as in the background population. This risk was elevated to 4.5% (95% CI 3.1-6.5%) conditional on hematologic malignancy in a dizygotic co-twin and was even greater at 7.6% (95% CI 4.8-11.8%) if a monozygotic co-twin had a hematologic malignancy. Heritability of the liability to develop any hematologic malignancy was 24% (95% CI 14-33%). This estimate decreased across age, from approximately 55% at age 40 to about 20-25% after age 55, when it seems to stabilize. In this largest ever studied twin cohort with the longest follow-up, we found evidence for familial risk of hematologic malignancies. The discovery of decreasing familial predisposition with increasing age underscores the importance of cancer surveillance in families with hematological malignancies.
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http://dx.doi.org/10.3390/cancers13123023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234145PMC
June 2021

Sleep and lifestyle in young adult monozygotic twin pairs discordant for body mass index.

Sleep Health 2021 Jun 27. Epub 2021 Jun 27.

Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Obesity Center, Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.

Objectives: The causal nature of the sleep-obesity association is unclear. To control for potential confounding by genes and shared environment, we studied monozygotic twin pairs discordant for body mass index (BMI). First, we investigated sleep in relation to BMI. Second, we examined associations of objective and subjective sleep duration and sleep debt (objective or subjective sleep duration minus subjective sleep need) with eating behaviors and physical activity (PA).

Design: Cross-sectional study.

Setting: Finnish twins in everyday life circumstances.

Participants: Seventy-four healthy young adult monozygotic twin pairs, of whom 36 were BMI-discordant (∆BMI ≥ 3 kg/m).

Measurements: Clinical measurements estimated BMI and body composition. Sleep, eating, and PA behaviors were measured by self-report and actigraphy.

Results: Compared to co-twins with lower BMI, co-twins with higher BMI reported shorter sleep (P = .043), more snoring (P = .0093), and greater tiredness (P = .0013) and trended toward eveningness (P = .036). Actigraphy-measured sleep duration correlated highly within BMI-discordant twin pairs (r = 0.63, P = .004). Subjective sleep debt was consistently positively associated with disinhibited eating and binge eating, but not with BMI. Subjective and objective sleep debt had negative correlations with moderate-to-vigorous PA.

Conclusions: Twins with higher BMI showed less favorable sleep characteristics than their co-twins with lower BMI. Subjective sleep debt is a potential target for intervention to reduce eating and PA behaviors that promote weight gain. Experimental studies could elucidate mechanisms underlying tiredness in individuals with higher BMI and investigate causal relationships between sleep debt, BMI, and lifestyle.
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http://dx.doi.org/10.1016/j.sleh.2021.04.002DOI Listing
June 2021

Genome-wide association studies identify 137 genetic loci for DNA methylation biomarkers of aging.

Genome Biol 2021 06 29;22(1):194. Epub 2021 Jun 29.

Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA.

Background: Biological aging estimators derived from DNA methylation data are heritable and correlate with morbidity and mortality. Consequently, identification of genetic and environmental contributors to the variation in these measures in populations has become a major goal in the field.

Results: Leveraging DNA methylation and SNP data from more than 40,000 individuals, we identify 137 genome-wide significant loci, of which 113 are novel, from genome-wide association study (GWAS) meta-analyses of four epigenetic clocks and epigenetic surrogate markers for granulocyte proportions and plasminogen activator inhibitor 1 levels, respectively. We find evidence for shared genetic loci associated with the Horvath clock and expression of transcripts encoding genes linked to lipid metabolism and immune function. Notably, these loci are independent of those reported to regulate DNA methylation levels at constituent clock CpGs. A polygenic score for GrimAge acceleration showed strong associations with adiposity-related traits, educational attainment, parental longevity, and C-reactive protein levels.

Conclusion: This study illuminates the genetic architecture underlying epigenetic aging and its shared genetic contributions with lifestyle factors and longevity.
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http://dx.doi.org/10.1186/s13059-021-02398-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243879PMC
June 2021

Correction to: Does the epigenetic clock GrimAge predict mortality independent of genetic influences: an 18 year follow-up study in older female twin pairs.

Clin Epigenetics 2021 Jun 25;13(1):130. Epub 2021 Jun 25.

Faculty of Sport and Health Sciences, Gerontology Research Center (GEREC), University of Jyväskylä, P.O. Box 35 (VIV), 40014, Jyväskylä, Finland.

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http://dx.doi.org/10.1186/s13148-021-01118-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234647PMC
June 2021

The Associations Between Leisure-Time Physical Activity and Academic Performance: A Twin Study.

J Phys Act Health 2021 Jun 17:1-6. Epub 2021 Jun 17.

Background: Both genetic and environmental influences have been shown to contribute to the association between physical activity and overall academic performance. The authors examined whether leisure-time physical activity (LTPA) shares genetic and environmental variances between spelling, essay writing, reading aloud, reading comprehension, and mathematics in early adolescence. Moreover, they investigated whether genetic polymorphisms associated with physical activity behavior affect these academic skills.

Methods: Participants were 12-year-old Finnish twins (n = 4356-4370 twins/academic skill, 49% girls). Academic skills were assessed by teachers, and LTPA was self-reported. Polygenic scores for physical activity behavior were constructed from the UK Biobank. Quantitative genetic modeling and linear regression models were used to analyze the data.

Results: The trait correlations between LTPA and academic skills were significant but weak (r = .05-.08). The highest trait correlation was found between LTPA and mathematics. A significant genetic correlation was revealed between LTPA and essay writing (rA = .14). Regarding polygenic scores of physical activity, the highest correlations were found with reading comprehension, spelling, and essay writing, but these results only approached statistical significance (P values = .09-.15).

Conclusions: The authors' results suggest that reading and writing are the academic skills that most likely share a common genetic background with LTPA.
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http://dx.doi.org/10.1123/jpah.2020-0746DOI Listing
June 2021

Does the epigenetic clock GrimAge predict mortality independent of genetic influences: an 18 year follow-up study in older female twin pairs.

Clin Epigenetics 2021 Jun 13;13(1):128. Epub 2021 Jun 13.

Faculty of Sport and Health Sciences, Gerontology Research Center (GEREC), University of Jyväskylä, P.O. Box 35 (VIV), 40014, Jyväskylä, Finland.

Background: Epigenetic clocks are based on DNA methylation (DNAm). It has been suggested that these clocks are useable markers of biological aging and premature mortality. Because genetic factors explain variations in both epigenetic aging and mortality, this association could also be explained by shared genetic factors. We investigated the influence of genetic and lifestyle factors (smoking, alcohol consumption, physical activity, chronic diseases, body mass index) and education on the association of accelerated epigenetic aging with mortality using a longitudinal twin design. Utilizing a publicly available online tool, we calculated the epigenetic age using two epigenetic clocks, Horvath DNAmAge and DNAm GrimAge, in 413 Finnish twin sisters, aged 63-76 years, at the beginning of the 18-year mortality follow-up. Epigenetic age acceleration was calculated as the residuals from a linear regression model of epigenetic age estimated on chronological age (AA, AA, respectively). Cox proportional hazard models were conducted for individuals and twin pairs.

Results: The results of the individual-based analyses showed an increased mortality hazard ratio (HR) of 1.31 (CI: 1.13-1.53) per one standard deviation (SD) increase in AA. The results indicated no significant associations of AA with mortality. Pairwise mortality analyses showed an HR of 1.50 (CI: 1.02-2.20) per 1 SD increase in AA. However, after adjusting for smoking, the HR attenuated substantially and was statistically non-significant (1.29; CI: 0.84-1.99). Similarly, in multivariable adjusted models the HR (1.42-1.49) was non-significant. In AA, the non-significant HRs were lower among monozygotic pairs in comparison to dizygotic pairs, while in AA there were no systematic differences by zygosity. Further, the pairwise analysis in quartiles showed that the increased within pair difference in AA was associated with a higher all-cause mortality risk.

Conclusions: In conclusion, the findings suggest that DNAm GrimAge is a strong predictor of mortality independent of genetic influences. Smoking, which is known to alter DNAm levels and is built into the DNAm GrimAge algorithm, attenuated the association between epigenetic aging and mortality risk.
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http://dx.doi.org/10.1186/s13148-021-01112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201844PMC
June 2021

Variants associated with expression have sex-differential effects on lung function.

Wellcome Open Res 2020 24;5:111. Epub 2021 May 24.

Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, EH4 2XU, UK.

Lung function is highly heritable and differs between the sexes throughout life. However, little is known about sex-differential genetic effects on lung function. We aimed to conduct the first genome-wide genotype-by-sex interaction study on lung function to identify genetic effects that differ between males and females. We tested for interactions between 7,745,864 variants and sex on spirometry-based measures of lung function in UK Biobank (N=303,612), and sought replication in 75,696 independent individuals from the SpiroMeta consortium. Five independent single-nucleotide polymorphisms (SNPs) showed genome-wide significant (P<5x10 ) interactions with sex on lung function, and 21 showed suggestive interactions (P<1x10 ). The strongest signal, from rs7697189 (chr4:145436894) on forced expiratory volume in 1 second (FEV ) (P=3.15x10 ), was replicated (P=0.016) in SpiroMeta. The C allele increased FEV more in males (untransformed FEV β=0.028 [SE 0.0022] litres) than females (β=0.009 [SE 0.0014] litres), and this effect was not accounted for by differential effects on height, smoking or pubertal age. rs7697189 resides upstream of the hedgehog-interacting protein ( ) gene and was previously associated with lung function and lung expression. We found expression was significantly different between the sexes (P=6.90x10 ), but we could not detect sex differential effects of rs7697189 on expression. We identified a novel genotype-by-sex interaction at a putative enhancer region upstream of the gene. Establishing the mechanism by which SNPs have different effects on lung function in males and females will be important for our understanding of lung health and diseases in both sexes.
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http://dx.doi.org/10.12688/wellcomeopenres.15846.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7938335.2PMC
May 2021

The genetic background of the associations between sense of coherence and mental health, self-esteem and personality.

Soc Psychiatry Psychiatr Epidemiol 2021 May 19. Epub 2021 May 19.

Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.

Purpose: Sense of coherence (SOC) represents coping and can be considered an essential component of mental health. SOC correlates with mental health and personality, but the background of these associations is poorly understood. We analyzed the role of genetic factors behind the associations of SOC with mental health, self-esteem and personality using genetic twin modeling and polygenic scores (PGS).

Methods: Information on SOC (13-item Orientation of Life Questionnaire), four mental health indicators, self-esteem and personality (NEO Five Factor Inventory Questionnaire) was collected from 1295 Finnish twins at 20-27 years of age.

Results: In men and women, SOC correlated negatively with depression, alexithymia, schizotypal personality and overall mental health problems and positively with self-esteem. For personality factors, neuroticism was associated with weaker SOC and extraversion, agreeableness and conscientiousness with stronger SOC. All these psychological traits were influenced by genetic factors with heritability estimates ranging from 19 to 66%. Genetic and environmental factors explained these associations, but the genetic correlations were generally stronger. The PGS of major depressive disorder was associated with weaker, and the PGS of general risk tolerance with stronger SOC in men, whereas in women the PGS of subjective well-being was associated with stronger SOC and the PGSs of depression and neuroticism with weaker SOC.

Conclusion: Our results indicate that a substantial proportion of genetic variation in SOC is shared with mental health, self-esteem and personality indicators. This suggests that the correlations between these traits reflect a common neurobiological background rather than merely the influence of external stressors.
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http://dx.doi.org/10.1007/s00127-021-02098-6DOI Listing
May 2021

Detection, treatment, and course of eating disorders in Finland: A population-based study of adolescent and young adult females and males.

Eur Eat Disord Rev 2021 Sep 18;29(5):720-732. Epub 2021 May 18.

Clinicum, Department of Public Health, University of Helsinki, Helsinki, Finland.

Objective: We assessed the detection, treatment and outcomes of DSM-5 eating disorders in a nationwide community setting.

Method: The FinnTwin12 cohort comprises twins born in 1983-1987 in Finland (n = 5,600), with follow-up starting at age 12. We outline treatment and outcomes of the 127 females and 15 males diagnosed with a lifetime DSM-5 eating disorder in interviews conducted for a subsample (n = 1,347) in their early 20s.

Results: Only 45 (32%) of those diagnosed with eating disorder in the interviews had their condition detected in healthcare, and even fewer received treatment (30% of females, 13% of males). Anorexia nervosa (AN), bulimia nervosa, and atypical AN were detected and treated more often than other eating disorders. Five years after disease onset, 41% of those diagnosed had recovered. There were no statistically significant differences in the course of different eating disorders (log-rank p = 0.66) but the outcome was more favourable among males (log-rank p = 0.008). The likelihood of 5-year recovery did not differ between those who had and who had not received treatment (41.1% vs. 40.5%, log-rank p = 0.66).

Conclusion: Although eating disorders are common and symptoms are persistent for many, they remain under-diagnosed and under-treated. In real-world settings, effectiveness of provided treatments may be limited.
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http://dx.doi.org/10.1002/erv.2838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8349843PMC
September 2021

Multi-polygenic Analysis of Nicotine Dependence in Individuals of European Ancestry.

Nicotine Tob Res 2021 May 19. Epub 2021 May 19.

Behavioral Genetics of Addiction Laboratory, Department of Psychology at Emory University, Atlanta GA.

Introduction: Heritability estimates of nicotine dependence (ND) range from 40-70%, but discovery GWAS of ND are underpowered and have limited predictive utility. In this work, we leverage genetically correlated traits and diseases to increase the accuracy of polygenic risk prediction.

Methods: We employed a multi-trait model using summary statistic-based best linear unbiased predictors (SBLUP) of genetic correlates of DSM-IV diagnosis of ND in 6,394 individuals of European Ancestry (prevalence = 45.3%, %female = 46.8%, µage = 40.08 [s.d. = 10.43]) and 3,061 individuals from a nationally-representative sample with Fagerström Test for Nicotine Dependence symptom count (FTND; 51.32% female, mean age = 28.9 [s.d. = 1.70]). Polygenic predictors were derived from GWASs known to be phenotypically and genetically correlated with ND (i.e., Cigarettes per Day (CPD), the Alcohol Use Disorders Identification Test (AUDIT-Consumption and AUDIT-Problems), Neuroticism, Depression, Schizophrenia, Educational Attainment, Body Mass Index (BMI), and Self-Perceived Risk-Taking); including Height as a negative control. Analyses controlled for age, gender, study site, and the first 10 ancestral principal components.

Results: The multi-trait model accounted for 3.6% of the total trait variance in DSM-IV ND. Educational Attainment (β=-0.125; 95% confidence interval (CI): [-0.149,-0.101]), CPD (0.071 [0.047,0.095]), and Self-Perceived Risk-Taking (0.051 [0.026,0.075]) were the most robust predictors. PGS effects on FTND were limited.

Conclusions: Risk for ND is not only polygenic, but also pleiotropic. Polygenic effects on ND that are accessible by these traits are limited in size and act additively to explain risk.
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http://dx.doi.org/10.1093/ntr/ntab105DOI Listing
May 2021

Blood and skeletal muscle ageing determined by epigenetic clocks and their associations with physical activity and functioning.

Clin Epigenetics 2021 May 17;13(1):110. Epub 2021 May 17.

Gerontology Research Center, Faculty of Sport and Health Sciences, University of Jyväskylä, P.O. Box 35 (VIV), 40014, Jyväskylä, Finland.

The aim of this study was to investigate the correspondence of different biological ageing estimates (i.e. epigenetic age) in blood and muscle tissue and their associations with physical activity (PA), physical function and body composition. Two independent cohorts (N = 139 and N = 47) were included, whose age span covered adulthood (23-69 years). Whole blood and m. vastus lateralis samples were collected, and DNA methylation was analysed. Four different DNA methylation age (DNAmAge) estimates were calculated using genome-wide methylation data and publicly available online tools. A novel muscle-specific methylation age was estimated using the R-package 'MEAT'. PA was measured with questionnaires and accelerometers. Several tests were conducted to estimate cardiorespiratory fitness and muscle strength. Body composition was estimated by dual-energy X-ray absorptiometry. DNAmAge estimates from blood and muscle were highly correlated with chronological age, but different age acceleration estimates were weakly associated with each other. The monozygotic twin within-pair similarity of ageing pace was higher in blood (r = 0.617-0.824) than in muscle (r = 0.523-0.585). Associations of age acceleration estimates with PA, physical function and body composition were weak in both tissues and mostly explained by smoking and sex. The muscle-specific epigenetic clock MEAT was developed to predict chronological age, which may explain why it did not associate with functional phenotypes. The Horvath's clock and GrimAge were weakly associated with PA and related phenotypes, suggesting that higher PA would be linked to accelerated biological ageing in muscle. This may, however, be more reflective of the low capacity of epigenetic clock algorithms to measure functional muscle ageing than of actual age acceleration. Based on our results, the investigated epigenetic clocks have rather low value in estimating muscle ageing with respect to the physiological adaptations that typically occur due to ageing or PA. Thus, further development of methods is needed to gain insight into muscle tissue-specific ageing and the underlying biological pathways.
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http://dx.doi.org/10.1186/s13148-021-01094-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8127311PMC
May 2021

Molecular pathways behind acquired obesity: Adipose tissue and skeletal muscle multiomics in monozygotic twin pairs discordant for BMI.

Cell Rep Med 2021 Apr 30;2(4):100226. Epub 2021 Mar 30.

Obesity Research Unit, Research Program for Clinical and Molecular Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Tissue-specific mechanisms prompting obesity-related development complications in humans remain unclear. We apply multiomics analyses of subcutaneous adipose tissue and skeletal muscle to examine the effects of acquired obesity among 49 BMI-discordant monozygotic twin pairs. Overall, adipose tissue appears to be more affected by excess body weight than skeletal muscle. In heavier co-twins, we observe a transcriptional pattern of downregulated mitochondrial pathways in both tissues and upregulated inflammatory pathways in adipose tissue. In adipose tissue, heavier co-twins exhibit lower creatine levels; in skeletal muscle, glycolysis- and redox stress-related protein and metabolite levels remain higher. Furthermore, metabolomics analyses in both tissues reveal that several proinflammatory lipids are higher and six of the same lipid derivatives are lower in acquired obesity. Finally, in adipose tissue, but not in skeletal muscle, mitochondrial downregulation and upregulated inflammation are associated with a fatty liver, insulin resistance, and dyslipidemia, suggesting that adipose tissue dominates in acquired obesity.
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http://dx.doi.org/10.1016/j.xcrm.2021.100226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080113PMC
April 2021

Substantial Within-Country Variation in the Incidence of Subarachnoid Hemorrhage: A Nationwide Finnish Study.

Neurology 2021 07 30;97(1):e52-e60. Epub 2021 Apr 30.

From the Department of Neurosurgery (I.R., M.K.), University of Helsinki and Helsinki University Hospital; Department of Public Health (I.R., J.V.L., J.K.), University of Helsinki, Finland; Department of Epidemiology and Public Health (J.V.L.), University College London, UK; and Institute for Molecular Medicine FIMM (J.K.), Helsinki, Finland.

Objective: To study whether the incidence of subarachnoid hemorrhage (SAH) varies between geographic regions of Finland.

Methods: By utilizing the nationwide Causes of Death and Hospital Discharge Registers, we identified all first-ever, hospitalized, and sudden-death (dying before hospitalization) SAH events in Finland between 1998 and 2017. Based on the patients' home residence, we divided SAHs into 5 geographic regions: southern, central, western, eastern, and northern Finland. We calculated crude and European age-standardized (European Standard Population [ESP] 2013) SAH incidence rates for each region and used a Poisson regression model to calculate age-, sex-, and calendar year-adjusted incidence rate ratios (IRRs) and 95% confidence intervals for regional and time-dependent differences.

Results: During the total 106,510,337 cumulative person-years, we identified 9,443 first-ever SAH cases, of which 24% resulted in death before hospitalization. As compared to western Finland, where the SAH incidence was the lowest (7.4 per 100,000 persons), the ESP-standardized SAH incidence was 1.4 times higher in eastern (10.2 per 100,000 persons; adjusted IRR, 1.37 [1.27-1.47]) and northern Finland (10.4 per 100,000 persons; adjusted IRR, 1.40 [1.30-1.51]). These differences were similar when men and women were analyzed independently. Although SAH incidence rates decreased in all 5 regions over 2 decades, the rate of decrease varied significantly by region.

Conclusion: SAH incidence appears to vary substantially by region in Finland. Our results suggest that regional SAH studies can identify high-risk subpopulations, but can also considerably over- or underestimate incidence on a nationwide level.
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http://dx.doi.org/10.1212/WNL.0000000000012129DOI Listing
July 2021

Teacher-rated aggression and co-occurring behaviors and emotional problems among schoolchildren in four population-based European cohorts.

PLoS One 2021 29;16(4):e0238667. Epub 2021 Apr 29.

Department of Biological Psychology, Faculty of Behavioural and Movement Sciences, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.

Aggressive behavior in school is an ongoing concern. The current focus is on specific manifestations such as bullying, but the behavior is broad and heterogenous. Children spend a substantial amount of time in school, but their behaviors in the school setting tend to be less well characterized than at home. Because aggression may index multiple behavioral problems, we used three validated instruments to assess means, correlations and gender differences of teacher-rated aggressive behavior with co-occurring externalizing/internalizing problems and social behavior in 39,936 schoolchildren aged 7-14 from 4 population-based cohorts from Finland, the Netherlands, and the UK. Correlations of aggressive behavior were high with all other externalizing problems (r: 0.47-0.80) and lower with internalizing problems (r: 0.02-0.39). A negative association was observed with prosocial behavior (r: -0.33 to -0.54). Mean levels of aggressive behavior differed significantly by gender. Despite the higher mean levels of aggressive behavior in boys, the correlations were notably similar for boys and girls (e.g., aggressive-hyperactivity correlations: 0.51-0.75 boys, 0.47-0.70 girls) and did not vary greatly with respect to age, instrument or cohort. Thus, teacher-rated aggressive behavior rarely occurs in isolation; boys and girls with problems of aggressive behavior likely require help with other behavioral and emotional problems. Important to note, higher aggressive behavior is not only associated with higher amounts of other externalizing and internalizing problems but also with lower levels of prosocial behavior.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0238667PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084195PMC
September 2021

IMI 2021 Yearly Digest.

Invest Ophthalmol Vis Sci 2021 04;62(5)

College of Optometry, University of Houston, Houston, Texas, United States.

Purpose: The International Myopia Institute (IMI) Yearly Digest highlights new research considered to be of importance since the publication of the first series of IMI white papers.

Methods: A literature search was conducted for articles on myopia between 2019 and mid-2020 to inform definitions and classifications, experimental models, genetics, interventions, clinical trials, and clinical management. Conference abstracts from key meetings in the same period were also considered.

Results: One thousand articles on myopia have been published between 2019 and mid-2020. Key advances include the use of the definition of premyopia in studies currently under way to test interventions in myopia, new definitions in the field of pathologic myopia, the role of new pharmacologic treatments in experimental models such as intraocular pressure-lowering latanoprost, a large meta-analysis of refractive error identifying 336 new genetic loci, new clinical interventions such as the defocus incorporated multisegment spectacles and combination therapy with low-dose atropine and orthokeratology (OK), normative standards in refractive error, the ethical dilemma of a placebo control group when myopia control treatments are established, reporting the physical metric of myopia reduction versus a percentage reduction, comparison of the risk of pediatric OK wear with risk of vision impairment in myopia, the justification of preventing myopic and axial length increase versus quality of life, and future vision loss.

Conclusions: Large amounts of research in myopia have been published since the IMI 2019 white papers were released. The yearly digest serves to highlight the latest research and advances in myopia.
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http://dx.doi.org/10.1167/iovs.62.5.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8088231PMC
April 2021

Factors contributing to psychological distress in the working population, with a special reference to gender difference.

BMC Public Health 2021 03 29;21(1):611. Epub 2021 Mar 29.

Department of Public Health and Welfare, Finnish Institute for Health and Welfare in Finland (THL), Helsinki, Finland.

Background: Psychological distress refers to non-specific symptoms of stress, anxiety and depression, and it is more common in women. Our aim was to investigate factors contributing to psychological distress in the working population, with a special reference to gender differences.

Methods: We used questionnaire data from the nationally representative Finnish Regional Health and Well-being Study (ATH) collected in the years 2012-2016 (target population participants aged 20 +, n = 96,668, response rate 53%), restricting the current analysis to those persons who were working full-time and under 65 of age (n = 34,468). Psychological distress was assessed using the Mental Health Inventory-5 (MHI-5) (cut-off value <=52). We studied the following factors potentially associated with psychological distress: sociodemographic factors, living alone, having children under18 years of age, lifestyle-related factors, social support, helping others outside of the home and work-related factors. We used logistic regression analysis to examine association between having work-family conflict with the likelihood for psychological distress. We first performed the models separately for men and women. Then interaction by gender was tested in the combined data for those independent variables where gender differences appeared probable in the analyses conducted separately for men and women.

Results: Women reported more psychological distress than men (11.0% vs. 8.8%, respectively, p < 0.0001). Loneliness, job dissatisfaction and family-work conflict were associated with the largest risk of psychological distress. Having children, active participation, being able to successfully combine work and family roles, and social support were found to be protective factors. A significant interaction with gender was found in only two variables: ignoring family due to being absorbed in one's work was associated with distress in women (OR 1.30 (95% CI 1.00-1.70), and mental strain of work in men (OR 2.71 (95% CI 1.66-4.41).

Conclusions: Satisfying work, family life and being able to successfully combine the two are important sources of psychological well-being for both genders in the working population.
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http://dx.doi.org/10.1186/s12889-021-10560-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8006634PMC
March 2021

Polygenic risk for obesity and its interaction with lifestyle and sociodemographic factors in European children and adolescents.

Int J Obes (Lond) 2021 06 22;45(6):1321-1330. Epub 2021 Mar 22.

Leibniz Institute for Prevention Research and Epidemiology-BIPS, Bremen, Germany.

Background: Childhood obesity is a complex multifaceted condition, which is influenced by genetics, environmental factors, and their interaction. However, these interactions have mainly been studied in twin studies and evidence from population-based cohorts is limited. Here, we analyze the interaction of an obesity-related genome-wide polygenic risk score (PRS) with sociodemographic and lifestyle factors for BMI and waist circumference (WC) in European children and adolescents.

Methods: The analyses are based on 8609 repeated observations from 3098 participants aged 2-16 years from the IDEFICS/I.Family cohort. A genome-wide polygenic risk score (PRS) was calculated using summary statistics from independent genome-wide association studies of BMI. Associations were estimated using generalized linear mixed models adjusted for sex, age, region of residence, parental education, dietary intake, relatedness, and population stratification.

Results: The PRS was associated with BMI (beta estimate [95% confidence interval (95%-CI)] = 0.33 [0.30, 0.37], r = 0.11, p value = 7.9 × 10) and WC (beta [95%-CI] = 0.36 [0.32, 0.40], r = 0.09, p value = 1.8 × 10). We observed significant interactions with demographic and lifestyle factors for BMI as well as WC. Children from Southern Europe showed increased genetic liability to obesity (BMI: beta [95%-CI] = 0.40 [0.34, 0.45]) in comparison to children from central Europe (beta [95%-CI] = 0.29 [0.23, 0.34]), p-interaction = 0.0066). Children of parents with a low level of education showed an increased genetic liability to obesity (BMI: beta [95%-CI] = 0.48 [0.38, 0.59]) in comparison to children of parents with a high level of education (beta [95%-CI] = 0.30 [0.26, 0.34]), p-interaction = 0.0012). Furthermore, the genetic liability to obesity was attenuated by a higher intake of fiber (BMI: beta [95%-CI] interaction = -0.02 [-0.04,-0.01]) and shorter screen times (beta [95%-CI] interaction = 0.02 [0.00, 0.03]).

Conclusions: Our results highlight that a healthy childhood environment might partly offset a genetic predisposition to obesity during childhood and adolescence.
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http://dx.doi.org/10.1038/s41366-021-00795-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159747PMC
June 2021

DNA methylation meta-analysis reveals cellular alterations in psychosis and markers of treatment-resistant schizophrenia.

Elife 2021 Feb 26;10. Epub 2021 Feb 26.

Department of Psychiatry and Psychotherapy, Jena University Hospital, Jena, Germany.

We performed a systematic analysis of blood DNA methylation profiles from 4483 participants from seven independent cohorts identifying differentially methylated positions (DMPs) associated with psychosis, schizophrenia, and treatment-resistant schizophrenia. Psychosis cases were characterized by significant differences in measures of blood cell proportions and elevated smoking exposure derived from the DNA methylation data, with the largest differences seen in treatment-resistant schizophrenia patients. We implemented a stringent pipeline to meta-analyze epigenome-wide association study (EWAS) results across datasets, identifying 95 DMPs associated with psychosis and 1048 DMPs associated with schizophrenia, with evidence of colocalization to regions nominated by genetic association studies of disease. Many schizophrenia-associated DNA methylation differences were only present in patients with treatment-resistant schizophrenia, potentially reflecting exposure to the atypical antipsychotic clozapine. Our results highlight how DNA methylation data can be leveraged to identify physiological (e.g., differential cell counts) and environmental (e.g., smoking) factors associated with psychosis and molecular biomarkers of treatment-resistant schizophrenia.
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http://dx.doi.org/10.7554/eLife.58430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009672PMC
February 2021

The associations of smoking dependence motives with depression among daily smokers.

Addiction 2021 08 24;116(8):2162-2174. Epub 2021 Feb 24.

Institute for Molecular Medicine Finland (FIMM), University of Helsinki, PO. Box 20, 00014 University of Helsinki, Helsinki, Finland.

Aims: To investigate how strongly smoking dependence and smoking dependence motives are associated with depressive symptoms among daily smokers and if these associations are independent of measured confounders and shared familial factors.

Design: Cross-sectional individual-based and within-pair analyses.

Setting: Fourth wave of the population-based Finnish Twin Cohort conducted in 2011.

Participants: 918 daily smokers born 1945-1957 (48% men), mean age 59.5 years including 38 twin pairs discordant for depression.

Measurements: Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression scale with a cut off value ≥20 for depression. Smoking dependence was assessed using the Fagerström Test for Cigarette Dependence (FTCD) and smoking dependence motives with three subscales from the multi-dimensional Brief Wisconsin Inventory of Smoking Dependence Motives (WISDM): primary dependence motives (PDM), affective enhancement (AE), and Taste. Logistic regressions, using standardized scores of independent variables and adjusted for multiple confounders with correction for sampling as twin pairs, were used in the individual-based analyses. Conditional logistic regression was used to control for shared familial factors in discordant twin pairs.

Findings: Prevalence of depression was 18% (n = 163: 61 [14%] in men, n = 102 [22%] in women). Higher smoking dependence measured by the FTCD (OR 1.45; 95% CI 1.20, 1.75), and dependence motives measured by the PDM (1.56; 1.30, 1.87) and the AE (1.54; 1.28, 1.85) were associated with higher odds of depression. The associations remained after adjusting for individual confounders, except for neuroticism, which attenuated all associations. FTCD, PDM, and AE showed associations with depression within depression-discordant monozygotic pairs, suggesting an association independent of familial factors.

Conclusions: Depression appears to be associated with smoking dependence and smoking dependence motives related to heavy, automatic use and use to regulate affective states. The associations appear to be confounded or mediated by neuroticism but are independent of shared familial influences.
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http://dx.doi.org/10.1111/add.15390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8274496PMC
August 2021

Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS). Exercise training intervention in monozygotic twins discordant for body weight.

BMC Sports Sci Med Rehabil 2021 Feb 24;13(1):16. Epub 2021 Feb 24.

Turku PET Centre, University of Turku, P.O. Box 52, FIN-20521, Turku, Finland.

Background: Obesity and physical inactivity are major global public health concerns, both of which increase the risk of insulin resistance and type 2 diabetes. Regulation of glucose homeostasis involves cross-talk between the central nervous system, peripheral tissues, and gut microbiota, and is affected by genetics. Systemic cross-talk between brain, gut, and peripheral tissues in glucose homeostasis: effects of exercise training (CROSSYS) aims to gain new systems-level understanding of the central metabolism in human body, and how exercise training affects this cross-talk.

Methods: CROSSYS is an exercise training intervention, in which participants are monozygotic twins from pairs discordant for body mass index (BMI) and within a pair at least the other is overweight. Twins are recruited from three population-based longitudinal Finnish twin studies, including twins born in 1983-1987, 1975-1979, and 1945-1958. The participants undergo 6-month-long exercise intervention period, exercising four times a week (including endurance, strength, and high-intensity training). Before and after the exercise intervention, comprehensive measurements are performed in Turku PET Centre, Turku, Finland. The measurements include: two positron emission tomography studies (insulin-stimulated whole-body and tissue-specific glucose uptake and neuroinflammation), magnetic resonance imaging (brain morphology and function, quantification of body fat masses and organ volumes), magnetic resonance spectroscopy (quantification of fat within heart, pancreas, liver and tibialis anterior muscle), echocardiography, skeletal muscle and adipose tissue biopsies, a neuropsychological test battery as well as biosamples from blood, urine and stool. The participants also perform a maximal exercise capacity test and tests of muscular strength.

Discussion: This study addresses the major public health problems related to modern lifestyle, obesity, and physical inactivity. An eminent strength of this project is the possibility to study monozygotic twin pairs that share the genome at the sequence level but are discordant for BMI that is a risk factor for metabolic impairments such as insulin resistance. Thus, this exercise training intervention elucidates the effects of obesity on metabolism and whether regular exercise training is able to reverse obesity-related impairments in metabolism in the absence of the confounding effects of genetic factors.

Trial Registration: ClinicalTrials.gov , NCT03730610 . Prospectively registered 5 November 2018.
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http://dx.doi.org/10.1186/s13102-021-00241-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905681PMC
February 2021

Polygenic burden has broader impact on health, cognition, and socioeconomic outcomes than most rare and high-risk copy number variants.

Mol Psychiatry 2021 Feb 1. Epub 2021 Feb 1.

Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.

Copy number variants (CNVs) are associated with syndromic and severe neurological and psychiatric disorders (SNPDs), such as intellectual disability, epilepsy, schizophrenia, and bipolar disorder. Although considered high-impact, CNVs are also observed in the general population. This presents a diagnostic challenge in evaluating their clinical significance. To estimate the phenotypic differences between CNV carriers and non-carriers regarding general health and well-being, we compared the impact of SNPD-associated CNVs on health, cognition, and socioeconomic phenotypes to the impact of three genome-wide polygenic risk score (PRS) in two Finnish cohorts (FINRISK, n = 23,053 and NFBC1966, n = 4895). The focus was on CNV carriers and PRS extremes who do not have an SNPD diagnosis. We identified high-risk CNVs (DECIPHER CNVs, risk gene deletions, or large [>1 Mb] CNVs) in 744 study participants (2.66%), 36 (4.8%) of whom had a diagnosed SNPD. In the remaining 708 unaffected carriers, we observed lower educational attainment (EA; OR = 0.77 [95% CI 0.66-0.89]) and lower household income (OR = 0.77 [0.66-0.89]). Income-associated CNVs also lowered household income (OR = 0.50 [0.38-0.66]), and CNVs with medical consequences lowered subjective health (OR = 0.48 [0.32-0.72]). The impact of PRSs was broader. At the lowest extreme of PRS for EA, we observed lower EA (OR = 0.31 [0.26-0.37]), lower-income (OR = 0.66 [0.57-0.77]), lower subjective health (OR = 0.72 [0.61-0.83]), and increased mortality (Cox's HR = 1.55 [1.21-1.98]). PRS for intelligence had a similar impact, whereas PRS for schizophrenia did not affect these traits. We conclude that the majority of working-age individuals carrying high-risk CNVs without SNPD diagnosis have a modest impact on morbidity and mortality, as well as the limited impact on income and educational attainment, compared to individuals at the extreme end of common genetic variation. Our findings highlight that the contribution of traditional high-risk variants such as CNVs should be analyzed in a broader genetic context, rather than evaluated in isolation.
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http://dx.doi.org/10.1038/s41380-021-01026-zDOI Listing
February 2021

Response by Rautalin et al Letter Regarding Article, "Smoking Causes Fatal Subarachnoid Hemorrhage: A Case-Control Study of Finnish Twins".

Stroke 2021 Jan 25;52(2):e74-e75. Epub 2021 Jan 25.

Institute for Molecular Medicine Finland FIMM, University of Helsinki (J.K.).

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http://dx.doi.org/10.1161/STROKEAHA.120.033235DOI Listing
January 2021
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