Browsing by Subject "HERITABILITY"

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  • Weiss, Alexander; Baselmans, Bart M. L.; Hofer, Edith; Yang, Jingyun; Okbay, Aysu; Lind, Penelope A.; Miller, Mike B.; Nolte, Ilja M.; Zhao, Wei; Hagenaars, Saskia P.; Hottenga, Jouke-Jan; Matteson, Lindsay K.; Snieder, Harold; Faul, Jessica D.; Hartman, Catharina A.; Boyle, Patricia A.; Tiemeier, Henning; Mosing, Miriam A.; Pattie, Alison; Davies, Gail; Liewald, David C.; Schmidt, Reinhold; De Jager, Philip L.; Heath, Andrew C.; Jokela, Markus; Starr, John M.; Oldehinkel, Albertine J.; Johannesson, Magnus; Cesarini, David; Hofman, Albert; Harris, Sarah E.; Smith, Jennifer A.; Keltikangas-Järvinen, Liisa; Pulkki-Råback, Laura; Schmidt, Helena; Smith, Jacqui; Iacono, William G.; McGue, Matt; Bennett, David A.; Pedersen, Nancy L.; Magnusson, Patrik K. E.; Deary, Ian J.; Martin, Nicholas G.; Boomsma, Dorret I.; Bartels, Meike; Luciano, Michelle (2016)
    Approximately half of the variation in wellbeing measures overlaps with variation in personality traits. Studies of non-human primate pedigrees and human twins suggest that this is due to common genetic influences. We tested whether personality polygenic scores for the NEO Five-Factor Inventory (NEO-FFI) domains and for item response theory (IRT) derived extraversion and neuroticism scores predict variance in wellbeing measures. Polygenic scores were based on published genome-wide association (GWA) results in over 17,000 individuals for the NEO-FFI and in over 63,000 for the IRT extraversion and neuroticism traits. The NEO-FFI polygenic scores were used to predict life satisfaction in 7 cohorts, positive affect in 12 cohorts, and general wellbeing in 1 cohort (maximal N = 46,508). Meta-analysis of these results showed no significant association between NEO-FFI personality polygenic scores and the wellbeing measures. IRT extraversion and neuroticism polygenic scores were used to predict life satisfaction and positive affect in almost 37,000 individuals from UK Biobank. Significant positive associations (effect sizes
  • Nichols, Hazel J.; Arbuckle, Kevin; Sanderson, Jennifer L.; Vitikainen, Emma I. K.; Marshall, Harry H.; Thompson, Faye J.; Cant, Michael A.; Wells, David A. (2021)
    Personality traits, such as the propensity to cooperate, are often inherited from parents to offspring, but the pathway of inheritance is unclear. Traits could be inherited via genetic or parental effects, or culturally via social learning from role models. However, these pathways are difficult to disentangle in natural systems as parents are usually the source of all of these effects. Here, we exploit natural 'cross fostering' in wild banded mongooses to investigate the inheritance of cooperative behaviour. Our analysis of 800 adult helpers over 21 years showed low but significant genetic heritability of cooperative personalities in males but not females. Cross fostering revealed little evidence of cultural heritability: offspring reared by particularly cooperative helpers did not become more cooperative themselves. Our results demonstrate that cooperative personalities are not always highly heritable in wild, and that the basis of behavioural traits can vary within a species (here, by sex).
  • Huusko, Johanna M.; Karjalainen, Minna K.; Mahlman, Mari; Haataja, Ritva; Kari, M. Anneli; Andersson, Sture; Toldi, Gergely; Tammela, Outi; Ramet, Mika; Lavoie, Pascal M.; Hallman, Mikko (2014)
  • Noreikiene, Kristina; Kuparinen, Anna; Merilae, Juha (2017)
    Telomeres are highly conserved nucleoprotein structures which protect genome integrity. The length of telomeres is influenced by both genetic and environmental factors, but relatively little is known about how different hereditary and environmental factors interact in determining telomere length. We manipulated growth rates and timing of maturation by exposing full-sib nine-spined sticklebacks (Pungitius pungitius) to two different temperature treatments and quantified the effects of temperature treatments, sex, timing of maturation, growth rate and family (genetic influences) on telomere length. We did not find the overall effect of temperature treatment on the relative telomere length. However, we found that variation in telomere length was related to timing of maturation in a sex- and temperature-dependent manner. Telomere length was negatively related to age at maturation in elevated temperature and early maturing males and females differed in telomere length. Variation in growth rate did not explain any variation in telomere length. The broad sense heritability (h(2)) of telomere length was estimated at h(2) = 0.31 - 0.47, suggesting predominance of environmental over genetic determinants of telomere length variability. This study provides the first evidence that age at maturation together with factors associated with it are influencing telomere length in an ectotherm. Future studies are encouraged to identify the extent to which these results can be replicated in other ectotherms.
  • Wang, Zhiyang; Whipp, Alyce; Heinonen-Guzejev, Marja; Kaprio, Jaakko (2022)
    Living in the same household exposes family members to shared environments and may be reflected in estimates of shared environment in twin analyses. The age at the separation of cotwins in a twin pair marks the end of such shared exposure, and the age of separation is commonly self-reported in studies. The objective of the study was to summarize the age at separation from residential records and use it to validate with self-reported separation status and age at the third and fourth wave of data collection in the FinnTwin12 cohort. Age at separation was generated from the address information, linking it to the Finnish Population information system since birth. Descriptive statistics by sex and zygosity are presented. The mean age at separation from residential records was 20.36 years old. Women separated earlier than men and dizygotic pairs earlier than monozygotic pairs. We also calculated the sensitivity and specificity with the self-reported separation status at waves 3 and 4, and interrater reliability with the self-reported separation age at wave 4. Age at separation from residential records had a relatively poor agreement with the self-report. This work enables us to use a more precise and objective measure for the shared environment in future twin studies.
  • Direk, Nese; Williams, Stephanie; Smith, Jennifer A.; Ripke, Stephan; Air, Tracy; Amare, Azmeraw T.; Amin, Najaf; Baune, Bernhard T.; Bennett, David A.; Blackwood, Douglas H. R.; Boomsma, Dorret; Breen, Gerome; Buttenschon, Henriette N.; Byrne, Enda M.; Borglum, Anders D.; Castelao, Enrique; Cichon, Sven; Clarke, Toni-Kim; Cornelis, Marilyn C.; Dannlowski, Udo; De Jager, Philip L.; Demirkan, Ayse; Domenici, Enrico; van Duijn, Cornelia M.; Dunn, Erin C.; Eriksson, Johan G.; Esko, Tonu; Faul, Jessica D.; Ferrucci, Luigi; Fornage, Myriam; de Geus, Eco; Gill, Michael; Gordon, Scott D.; Grabe, Hans Joergen; van Grootheest, Gerard; Hamilton, Steven P.; Hartman, Catharina A.; Heath, Andrew C.; Hek, Karin; Hofman, Albert; Homuth, Georg; Horn, Carsten; Hottenga, Jouke Jan; Kardia, Sharon L. R.; Kloiber, Stefan; Koenen, Karestan; Kutalik, Zoltan; Ladwig, Karl-Heinz; Lahti, Jari; Levinson, Douglas F.; Lewis, Cathryn M.; Lewis, Glyn; Li, Qingqin S.; Llewellyn, David J.; Lucae, Susanne; Lunetta, Kathryn L.; MacIntyre, Donald J.; Madden, Pamela; Martin, Nicholas G.; McIntosh, Andrew M.; Metspalu, Andres; Milaneschi, Yuri; Montgomery, Grant W.; Mors, Ole; Mosley, Thomas H.; Murabito, Joanne M.; Mueller-Myhsok, Bertram; Nothen, Markus M.; Nyholt, Dale R.; O'Donovan, Michael C.; Penninx, Brenda W.; Pergadia, Michele L.; Perlis, Roy; Potash, James B.; Preisig, Martin; Purcell, Shaun M.; Quiroz, Jorge A.; Raikkonen, Katri; Rice, John P.; Rietschel, Marcella; Rivera, Margarita; Schulze, Thomas G.; Shi, Jianxin; Shyn, Stanley; Sinnamon, Grant C.; Smit, Johannes H.; Smoller, Jordan W.; Snieder, Harold; Tanaka, Toshiko; Tansey, Katherine E.; Teumer, Alexander; Uher, Rudolf; Umbricht, Daniel; Van der Auwera, Sandra; Ware, Erin B.; Weir, David R.; Weissman, Myrna M.; Willemsen, Gonneke; Yang, Jingyun; Zhao, Wei; Tiemeier, Henning; Sullivan, Patrick F. (2017)
    BACKGROUND: The genetics of depression has been explored in genome-wide association studies that focused on either major depressive disorder or depressive symptoms with mostly negative findings. A broad depression phenotype including both phenotypes has not been tested previously using a genome-wide association approach. We aimed to identify genetic polymorphisms significantly associated with a broad phenotype from depressive symptoms to major depressive disorder. METHODS: We analyzed two prior studies of 70,017 participants of European ancestry from general and clinical populations in the discovery stage. We performed a replication meta-analysis of 28,328 participants. Single nucleotide polymorphism (SNP)-based heritability and genetic correlations were calculated using linkage disequilibrium score regression. Discovery and replication analyses were performed using a p-value-based meta-analysis. Lifetime major depressive disorder and depressive symptom scores were used as the outcome measures. RESULTS: The SNP-based heritability of major depressive disorder was 0.21 (SE = 0.02), the SNP-based heritability of depressive symptoms was 0.04 (SE = 0.01), and their genetic correlation was 1.001 (SE = 0.2). We found one genome-wide significant locus related to the broad depression phenotype (rs9825823, chromosome 3: 61,082,153, p = 8.2 x 10(-9)) located in an intron of the FHIT gene. We replicated this SNP in independent samples (p = .02) and the overall meta-analysis of the discovery and replication cohorts (1.0 x 10(-9)). CONCLUSIONS: This large study identified a new locus for depression. Our results support a continuum between depressive symptoms and major depressive disorder. A phenotypically more inclusive approach may help to achieve the large sample sizes needed to detect susceptibility loci for depression.
  • PRACTICAL Consortium; Law, Philip J.; Timofeeva, Maria; Fernandez-Rozadilla, Ceres; Palin, Kimmo; Hänninen, Ulrika A.; Cajuso, Tatiana; Tanskanen, Tomas; Kondelin, Johanna; Kaasinen, Eevi; Sarin, Antti-Pekka; Eriksson, Johan G.; Jousilahti, Pekka; Ripatti, Samuli; Palotie, Aarno; Renkonen-Sinisalo, Laura; Lepistö, Anna; Aaltonen, Lauri A.; Rissanen, Harri; Salomaa, Veikko; Böhm, Jan; Mecklin, Jukka-Pekka; Pukkala, Eero (2019)
    Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide, and has a strong heritable basis. We report a genome-wide association analysis of 34,627 CRC cases and 71,379 controls of European ancestry that identifies SNPs at 31 new CRC risk loci. We also identify eight independent risk SNPs at the new and previously reported European CRC loci, and a further nine CRC SNPs at loci previously only identified in Asian populations. We use in situ promoter capture Hi-C (CHi-C), gene expression, and in silico annotation methods to identify likely target genes of CRC SNPs. Whilst these new SNP associations implicate target genes that are enriched for known CRC pathways such as Wnt and BMP, they also highlight novel pathways with no prior links to colorectal tumourigenesis. These findings provide further insight into CRC susceptibility and enhance the prospects of applying genetic risk scores to personalised screening and prevention.
  • Sillanpää, Elina; Laakkonen, Eija K.; Vaara, Elina; Rantanen, Taina; Kovanen, Vuokko; Sipilä, Sarianna; Kaprio, Jaakko; Ollikainen, Miina (2018)
    Background: Biomarkers of biological aging - DNA methylation age (DNAm age) and leukocyte telomere length (LTL)-correlate strongly with chronological age across the life course. It is, however, unclear how these measures of cellular wear and tear are associated with muscle strength and functional capacity, which are known to decline with older age and are associated with mortality. We investigated if DNAm age and LTL were associated with body composition and physical functioning by examining 48 monozygotic twin sisters. Methods: White blood cell DNAm age (predicted years) was calculated from Illumina 450 k BeadChip methylation data using an online calculator. DNAm age acceleration was defined from the residuals derived from a linear regression model of DNAm age on chronological age. LTL was measured by qPCR. Total body percentage of fat and lean mass were estimated using bioimpedance. Physical functioning was measured by grip strength, knee extension strength and by 10 m maximal walking speed test. Results: In all participants, DNAm age (58.4 +/- 6.6) was lower than chronological age (61.3 +/- 5.9 years). Pairwise correlations of monozygotic co-twins were high for DNAm age (0.88, 95% CI 0.79, 0.97), age acceleration (0.68, 95% CI 0.30, 0.85) and LTL (0.77, 95% CI 0.60, 0.94). Increased age acceleration i.e. faster epigenetic aging compared to chronological age was associated with lower grip strength (beta = -5.3 SE 1.9 p = 0.011), but not with other measures of physical functioning or body composition. LTL was not associated with body composition or physical functioning. Conclusions: To conclude, accelerated DNAm age is associated with lower grip strength, a biomarker known to be associated with physiological aging, and which predicts decline in physical functioning and mortality. Further studies may clarify whether epigenetic aging explains the decline in muscle strength with aging or whether DNAm age just illustrates the progress of aging.
  • Skytthe, Axel; Harris, Jennifer R.; Czene, Kamila; Mucci, Lorelei; Adami, Hans-Olov; Christensen, Kaare; Hjelmborg, Jacob; Holm, Niels V.; Nilsen, Thomas S.; Kaprio, Jaakko; Pukkala, Eero (2019)
    The Nordic countries have comprehensive, population-based health and medical registries linkable on individually unique personal identity codes, enabling complete long-term follow-up. The aims of this study were to describe the NorTwinCan cohort established in 2010 and assess whether the cancer mortality and incidence rates among Nordic twins are similar to those in the general population. We analyzed approximately 260,000 same-sexed twins in the nationwide twin registers in Denmark, Finland, Norway and Sweden. Cancer incidence was determined using follow-up through the national cancer registries. We estimated standardized incidence (SIR) and mortality (SMR) ratios with 95% confidence intervals (CI) across country, age, period, follow-up time, sex and zygosity. More than 30,000 malignant neoplasms have occurred among the twins through 2010. Mortality rates among twins were slightly lower than in the general population (SMR 0.96; CI 95% [0.95, 0.97]), but this depends on information about zygosity. Twins have slightly lower cancer incidence rates than the general population, with SIRs of 0.97 (95% CI [0.96, 0.99]) in men and 0.96 (95% CI [0.94, 0.97]) in women. Testicular cancer occurs more often among male twins than singletons (SIR 1.15; 95% CI [1.02, 1.30]), while cancers of the kidney (SIR 0.82; 95% CI [0.76, 0.89]), lung (SIR 0.89; 95% CI [0.85, 0.92]) and colon (SIR 0.90; 95% CI [0.87, 0.94]) occur less often in twins than in the background population. Our findings indicate that the risk of cancer among twins is so similar to the general population that cancer risk factors and estimates of heritability derived from the Nordic twin registers are generalizable to the background populations.
  • Bartels, Meike; Hendriks, Anne; Mauri, Matteo; Krapohl, Eva; Whipp, Alyce; Bolhuis, Koen; Conde, Lucia Colodro; Luningham, Justin; Ip, Hill Fung; Hagenbeek, Fiona; Roetman, Peter; Gatej, Raluca; Lamers, Audri; Nivard, Michel; van Dongen, Jenny; Lu, Yi; Middeldorp, Christel; van Beijsterveldt, Toos; Vermeiren, Robert; Hankemeijer, Thomas; Kluft, Cees; Medland, Sarah; Lundstrom, Sebastian; Rose, Richard; Pulkkinen, Lea; Vuoksimaa, Eero; Korhonen, Tellervo; Martin, Nicholas G.; Lubke, Gitta; Finkenauer, Catrin; Fanos, Vassilios; Tiemeier, Henning; Lichtenstein, Paul; Plomin, Robert; Kaprio, Jaakko; Boomsma, Dorret I. (2018)
    Childhood aggression and its resulting consequences inflict a huge burden on affected children, their relatives, teachers, peers and society as a whole. Aggression during childhood rarely occurs in isolation and is correlated with other symptoms of childhood psychopathology. In this paper, we aim to describe and improve the understanding of the co-occurrence of aggression with other forms of childhood psychopathology. We focus on the co-occurrence of aggression and other childhood behavioural and emotional problems, including other externalising problems, attention problems and anxiety-depression. The data were brought together within the EU-ACTION (Aggression in Children: unravelling gene-environment interplay to inform Treatment and InterventiON strategies) project. We analysed the co-occurrence of aggression and other childhood behavioural and emotional problems as a function of the child's age (ages 3 through 16years), gender, the person rating the behaviour (father, mother or self) and assessment instrument. The data came from six large population-based European cohort studies from the Netherlands (2x), the UK, Finland and Sweden (2x). Multiple assessment instruments, including the Child Behaviour Checklist (CBCL), the Strengths and Difficulties Questionnaire (SDQ) and Multidimensional Peer Nomination Inventory (MPNI), were used. There was a good representation of boys and girls in each age category, with data for 30,523 3- to 4-year-olds (49.5% boys), 20,958 5- to 6-year-olds (49.6% boys), 18,291 7- to 8-year-olds (49.0% boys), 27,218 9- to 10-year-olds (49.4% boys), 18,543 12- to 13-year-olds (48.9% boys) and 10,088 15- to 16-year-olds (46.6% boys). We replicated the well-established gender differences in average aggression scores at most ages for parental ratings. The gender differences decreased with age and were not present for self-reports. Aggression co-occurred with the majority of other behavioural and social problems, from both externalising and internalising domains. At each age, the co-occurrence was particularly prevalent for aggression and oppositional and ADHD-related problems, with correlations of around 0.5 in general. Aggression also showed substantial associations with anxiety-depression and other internalizing symptoms (correlations around 0.4). Co-occurrence for self-reported problems was somewhat higher than for parental reports, but we found neither rater differences, nor differences across assessment instruments in co-occurrence patterns. There were large similarities in co-occurrence patterns across the different European countries. Finally, co-occurrence was generally stable across age and sex, and if any change was observed, it indicated stronger correlations when children grew older. We present an online tool to visualise these associations as a function of rater, gender, instrument and cohort. In addition, we present a description of the full EU-ACTION projects, its first results and the future perspectives.
  • Verta, Jukka-Pekka; Debes, Paul; Piavchenko, Nikolai; Ruokolainen, Annukka; Ovaskainen, Outi Sinikka; Moustakas-Verho, Jacqueline; Tillanen, Seija Iiris; Parre, Noora; Aykanat, Tutku; Erkinaro, Jaakko; Primmer, Craig (2020)
    A major goal in biology is to understand how evolution shapes variation in individual life histories. Genome-wide association studies have been successful in uncovering genome regions linked with traits underlying life history variation in a range of species. However, lack of functional studies of the discovered genotype-phenotype associations severely restrains our understanding how alternative life history traits evolved and are mediated at the molecular level. Here, we report acis-regulatory mechanism whereby expression of alternative isoforms of the transcription co-factorvestigial-like 3(vgll3) associate with variation in a key life history trait, age at maturity, in Atlantic salmon (Salmo salar). Using a common-garden experiment, we first show thatvgll3genotype associates with puberty timing in one-year-old salmon males. By way of temporal sampling ofvgll3expression in ten tissues across the first year of salmon development, we identify a pubertal transition invgll3expression where maturation coincided with a 66% reduction in testicularvgll3expression. Thelatematuration allele was not only associated with a tendency to delay puberty, but also with expression of a rare transcript isoform ofvgll3pre-puberty. By comparing absolutevgll3mRNA copies in heterozygotes we show that the expression difference between theearlyandlatematurity alleles is largelycis-regulatory. We propose a model whereby expression of a rare isoform from thelateallele shifts the liability of its carriers towards delaying puberty. These results exemplify the potential importance of regulatory differences as a mechanism for the evolution of life history traits. Author summary Alternative life history strategies are an important source of diversity within populations and promote the maintenance of adaptive capacity and population resilience. However, in many cases the molecular basis of different life history strategies remains elusive. Age at maturity is a key adaptive life history trait in Atlantic salmon and has a relatively simple genetic basis. Using salmon age at maturity as a model, we report a mechanism whereby different transcript isoforms of the key age at maturity gene,vestigial-like 3(vgll3), associate with variation in the timing of male puberty. Our results show how gene regulatory differences in conjunction with variation in gene transcript structure can encode for complex alternative life histories.
  • Sandholm, Niina; Haukka, Jani K.; Toppila, Iiro; Valo, Erkka; Harjutsalo, Valma; Forsblom, Carol; Groop, Per-Henrik (2018)
    Urinary albumin excretion is an early sign of diabetic kidney disease, affecting every third individual with diabetes. Despite substantial estimated heritability, only variants in the GLRA3 gene have been genome-wide significantly associated (p-value <5 x 10(-8)) with diabetic albuminuria, in Finnish individuals with type 1 diabetes; However, replication attempt in non-Finnish Europeans with type 1 diabetes showed nominally significant association in the opposite direction, suggesting a population-specific effect, but simultaneously leaving the finding controversial. In this study, the association between the common rs10011025 variant in the GLRA3 locus, and albuminuria, was confirmed in 1259 independent Finnish individuals with type 1 diabetes (p = 0.0013), and meta-analysis of all Finnish individuals yielded a genome-wide significant association. The association was particularly pronounced in subjects not reaching the treatment target for blood glucose levels (HbA(1c) > 7%; N = 2560, p = 1.7 x 10(-9)). Even though further studies are needed to pinpoint the causal variants, dissecting the association at the GLRA3 locus may uncover novel molecular mechanisms for diabetic albuminuria irrespective of population background.
  • Silventoinen, Karri; Jelenkovic, Aline; Sund, Reijo; Yokoyama, Yoshie; Hur, Yoon-Mi; Cozen, Wendy; Hwang, Amie E.; Mack, Thomas M.; Honda, Chika; Inui, Fujio; Iwatani, Yoshinori; Watanabe, Mikio; Tomizawa, Rie; Pietilainen, Kirsi H.; Rissanen, Aila; Siribaddana, Sisira H.; Hotopf, Matthew; Sumathipala, Athula; Rijsdijk, Fruhling; Tan, Qihua; Zhang, Dongfeng; Pang, Zengchang; Piirtola, Maarit; Aaltonen, Sari; Oncel, Sevgi Y.; Aliev, Fazil; Rebato, Esther; Hjelmborg, Jacob B.; Christensen, Kaare; Skytthe, Axel; Kyvik, Kirsten O.; Silberg, Judy L.; Eaves, Lindon J.; Cutler, Tessa L.; Ordonana, Juan R.; Sanchez-Romera, Juan F.; Colodro-Conde, Lucia; Song, Yun-Mi; Yang, Sarah; Lee, Kayoung; Franz, Carol E.; Kremen, William S.; Lyons, Michael J.; Busjahn, Andreas; Nelson, Tracy L.; Whitfield, Keith E.; Kandler, Christian; Jang, Kerry L.; Gatz, Margaret; Butler, David A.; Stazi, Maria A.; Fagnani, Corrado; D'Ippolito, Cristina; Duncan, Glen E.; Buchwald, Dedra; Martin, Nicholas G.; Medland, Sarah E.; Montgomery, Grant W.; Jeong, Hoe-Uk; Swan, Gary E.; Krasnow, Ruth; Magnusson, Patrik Ke; Pedersen, Nancy L.; Aslan, Anna K. Dahl; McAdams, Tom A.; Eley, Thalia C.; Gregory, Alice M.; Tynelius, Per; Baker, Laura A.; Tuvblad, Catherine; Bayasgalan, Gombojav; Narandalai, Danshiitsoodol; Spector, Timothy D.; Mangino, Massimo; Lachance, Genevieve; Burt, S. Alexandra; Klump, Kelly L.; Harris, Jennifer R.; Brandt, Ingunn; Nilsen, Thomas S.; Krueger, Robert F.; Mcgue, Matt; Pahlen, Shandell; Corley, Robin P.; Huibregtse, Brooke M.; Bartels, Meike; van Beijsterveldt, Catharina E. M.; Willemsen, Gonneke; Goldberg, Jack H.; Rasmussen, Finn; Tarnoki, Adam D.; Tarnoki, David L.; Derom, Catherine A.; Vlietinck, Robert F.; Loos, Ruth J. F.; Hopper, John L.; Sung, Joohon; Maes, Hermine H.; Turkheimer, Eric; Boomsma, Dorret I.; Sorensen, Thorkild I. A.; Kaprio, Jaakko (2017)
    Background: Genes and the environment contribute to variation in adult body mass index [BMI (in kg/m(2))], but factors modifying these variance components are poorly understood. Objective: We analyzed genetic and environmental variation in BMI between men and women from young adulthood to old age from the 1940s to the 2000s and between cultural-geographic regions representing high (North America and Australia), moderate (Europe), and low (East Asia) prevalence of obesity. Design: We used genetic structural equation modeling to analyze BMI in twins >= 20 y of age from 40 cohorts representing 20 countries (140,379 complete twin pairs). Results: The heritability of BMI decreased from 0.77 (95% CI: 0.77, 0.78) and 0.75 (95% CI: 0.74, 0.75) in men and women 2029 y of age to 0.57 (95% CI: 0.54, 0.60) and 0.59 (95% CI: 0.53, 0.65) in men 70-79 y of age and women 80 y of age, respectively. The relative influence of unique environmental factors correspondingly increased. Differences in the sets of genes affecting BMI in men and women increased from 20-29 to 60-69 y of age. Mean BMI and variances in BMI increased from the 1940s to the 2000s and were greatest in North America and Australia, followed by Europe and East Asia. However, heritability estimates were largely similar over measurement years and between regions. There was no evidence of environmental factors shared by co-twins affecting BMI. Conclusions: The heritability of BMI decreased and differences in the sets of genes affecting BMI in men and women increased from young adulthood to old age. The heritability of BMI was largely similar between cultural-geographic regions and measurement years, despite large differences in mean BMI and variances in BMI. Our results show a strong influence of genetic factors on BMI, especially in early adulthood, regardless of the obesity level in the population.
  • Sillanpaa, Elina; Tormakangas, Timo; Rantanen, Taina; Kaprio, Jaakko; Sipila, Sarianna (2016)
    Leukocyte telomere length (LTL) is known to be associated with mortality, but its association with age-related decline in physical functioning and the development of disability is less clear. This study examined the associations between LTL and physical functioning, and investigated whether LTL predicts level of physical functioning over an 11-year follow-up. Older mono-(MZ) and dizygotic (DZ) twin sisters (n = 386) participated in the study. Relative LTL was measured by qPCR at baseline. Physical functioning was measured by 6-min walking distance and level of physical activity (PA). Walking distance was measured at baseline and at 3-year follow-up. PA was assessed by questionnaire at baseline and at 3- and 11-year follow-ups. The baseline analysis was performed with path models, adjusted with age and within-pair dependence of twin pairs. The longitudinal analysis was performed with a repeated measures linear model adjusted for age and longitudinal within-pair dependence. A nonrandom missing data analysis was utilized. At baseline, in all individuals, LTL was associated with PA (est. 0.14, SE 0.06, p = 0.011), but not with walking distance. Over the follow-up, a borderline significant association was observed between LTL and walking distance (est. 0.14, SE 0.07, p = 0.060) and a significant association between LTL and PA (est. 0.19, SE 0.06, p = 0.001). The results suggest that LTL is associated with PA and may, therefore, serve as a biomarker predicting the development of disability. Longitudinal associations between LTL and PA were observed only when nonrandom data missingness was taken into account in the analysis.
  • Föhr, Tiina; Waller, Katja; Viljanen, Anne; Sanchez, Riikka; Ollikainen, Miina; Rantanen, Taina; Kaprio, Jaakko; Sillanpää, Elina (2021)
    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(Horvath), AA(GrimAge), 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 (CI95: 1.13-1.53) per one standard deviation (SD) increase in AA(GrimAge). The results indicated no significant associations of AA(Horvath) with mortality. Pairwise mortality analyses showed an HR of 1.50 (CI95: 1.02-2.20) per 1 SD increase in AA(GrimAge). However, after adjusting for smoking, the HR attenuated substantially and was statistically non-significant (1.29; CI95: 0.84-1.99). Similarly, in multivariable adjusted models the HR (1.42-1.49) was non-significant. In AA(Horvath), the non-significant HRs were lower among monozygotic pairs in comparison to dizygotic pairs, while in AA(GrimAge) there were no systematic differences by zygosity. Further, the pairwise analysis in quartiles showed that the increased within pair difference in AA(GrimAge) 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.
  • Vatka, Emma; Orell, Markku; Rytkönen, Seppo; Merilä, Juha (2021)
    Many populations need to adapt to changing environmental conditions, such as warming climate. Changing conditions generate directional selection for traits critical for fitness. For evolutionary responses to occur, these traits need to be heritable. However, changes in environmental conditions can alter the amount of heritable variation a population expresses, making predictions about expected responses difficult. The aim of this study was to evaluate the effects of ambient temperatures on evolutionary potential and strength of natural selection on the timing of reproduction in two passerine birds breeding in boreal forests. Long-term data on individually marked Willow Tits Poecile montanus (1975-2018) and Great Tits Parus major (1969-2018) were analysed with random regression animal models to assess if spring temperatures affect the expressed amount of additive genetic variation (V-A) and heritability (h(2)) in the timing of breeding. We assessed if ambient temperatures of different seasons influenced the direction and strength of selection on breeding time. We also evaluated if the strength of selection covaried with evolutionary potential. Levels of V-A or h(2) expressed in laying date were unaffected by spring temperatures in both study species. Selection for earlier breeding was found in the Willow Tit, but not in the Great Tit. In the Willow Tit, selection for earlier breeding was more intense when the temperatures of following autumns and winters were low. Different measures of evolutionary potential did not covary strongly with the strength of selection in either species. We conclude that there is no or little evidence that climate warming would either constrain or promote evolutionary potential in timing of breeding through changes in amount of genetic variance expressed in boreal Willow and Great Tits. However, selection on the timing of breeding, a life-history event taking place in springtime, is regulated by temperatures of autumns and winters. Rapid warming of these periods have thus potential to reduce the rate of expected evolutionary response in reproductive timing.
  • Merikanto, Ilona; Partonen, Timo (2021)
    Background Epidemiological data show that having the eveningness associates with poor mental health. For preventive measures it is important to know which underlying factors mediate these associations and the burden posed to public health. This study examines at a population-based level, whether (1) circadian type and the sleep-wake behavior-based phase entrainment similarly associate with mental health problems, (2) there are differences in hospital treatments due to mental disorders between chronotypes, and (3) the association of chronotype with mental health is mediated by insufficient sleep. Methods The study sample (N = 18,039) consisted of population-based sample of Finnish adults, aged 25-74 years, with information on their circadian type and sleep patterns, mental health symptoms, and diagnosis as reported in a health examination survey, as well as hospital treatments as recorded on the national Hospital Discharge Register. Results All the mental health symptoms, diagnoses and hospital treatments were more pronounced among Evening-types, especially when assessed by circadian type. Insufficient sleep mediated most but not all of the associations between eveningness and mental health. Conclusions Eveningness does not increase mental health risks only on symptom or diagnosis level, but also on hospital admission level. A higher prevalence of insufficient sleep among the Evening-types elevates the risk and severity for many of the mental health outcomes. Improving the sleep among Evening-types could help to improve their mental health prospective and ease the health care burden.
  • McQuillan, Ruth; Eklund, Niina; Pirastu, Nicola; Kuningas, Maris; McEvoy, Brian P.; Esko, Tonu; Corre, Tanguy; Davies, Gail; Kaakinen, Marika; Lyytikainen, Leo-Pekka; Kristiansson, Kati; Havulinna, Aki S.; Gogele, Martin; Vitart, Veronique; Tenesa, Albert; Aulchenko, Yurii; Hayward, Caroline; Johansson, Asa; Boban, Mladen; Ulivi, Sheila; Robino, Antonietta; Boraska, Vesna; Igl, Wilmar; Wild, Sarah H.; Zgaga, Lina; Amin, Najaf; Theodoratou, Evropi; Polasek, Ozren; Girotto, Giorgia; Lopez, Lorna M.; Sala, Cinzia; Lahti, Jari; Laatikainen, Tiina; Prokopenko, Inga; Kals, Mart; Viikari, Jorma; Yang, Jian; Pouta, Anneli; Estrada, Karol; Hofman, Albert; Freimer, Nelson; Martin, Nicholas G.; Kahonen, Mika; Milani, Lili; Heliovaara, Markku; Räikkönen, Katri; Widen, Elisabeth; Koskinen, Seppo; Eriksson, Johan G.; Perola, Markus; ROHgen Consortium (2012)
  • Class, Barbara; Kluen, Edward; Brommer, Jon E. (2014)
    Behavioral differences between individuals that are consistent over time characterize animal personality. The existence of such consistency contrasts to the expectation based on classical behavioral theory that facultative behavior maximizes individual fitness. Here, we study two personality traits (aggression and breath rate during handling) in a wild population of blue tits during 2007– 2012. Handling aggression and breath rate were moderately heritable (h2 = 0.35 and 0.20, respectively) and not genetically correlated (rA = 0.06) in adult blue tits, which permits them to evolve independently. Reciprocal cross-fostering (2007–2010) showed that offspring reared by more aggressive males have a higher probability to recruit. In addition, offspring reared by pairs mated assortatively for handling aggression had a higher recruitment probability, which is the first evidence that both parents’ personalities influence their reproductive success in the wild in a manner independent of their genetic effects. Handling aggression was not subjected to survival selection in either sex, but slow-breathing females had a higher annual probability of survival as revealed by capture–mark–recapture analysis. We find no evidence for temporal fluctuations in selection, and thus conclude that directional selection (via different fitness components) acts on these two heritable personality traits. Our findings show that blue tit personality has predictable fitness consequences, but that facultative adjustment of an individual’s personality to match the fitness maximum is likely constrained by the genetic architecture of personality. In the face of directional selection, the presence of heritable variation in personality suggests the existence of a trade-off that we have not identified yet.
  • CHD Exome Consortium; Consortium Genetics Smoking; EPIC-CVD Consortium; Understanding Soc Sci Grp; Brazel, David M.; Jiang, Yu; Hughey, Jordan M.; Loukola, Anu; Qaiser, Beenish; Kaprio, Jaakko; Kontto, Jukka; Perola, Markus; Dunning, Alison M. (2019)
    BACKGROUND: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. METHODS: We analyzed similar to 250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. RESULTS: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. CONCLUSIONS: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.