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The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have “non-specific effects” affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I–III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure. The current framework for testing and regulating vaccines was established before the realization that vaccines, in addition to their effect against the vaccine-specific disease, may also have "non-specific effects" affecting the risk of unrelated diseases. Accumulating evidence from epidemiological studies shows that vaccines in some situations can affect all-cause mortality and morbidity in ways that are not explained by the prevention of the vaccine-targeted disease. Live attenuated vaccines have sometimes been associated with decreases in mortality and morbidity that are greater than anticipated. In contrast, some non-live vaccines have in certain contexts been associated with increases in all-cause mortality and morbidity. The non-specific effects are often greater for female than male individuals. Immunological studies have provided several mechanisms that explain how vaccines might modulate the immune response to unrelated pathogens, such as through trained innate immunity, emergency granulopoiesis, and heterologous T-cell immunity. These insights suggest that the framework for the testing, approving, and regulating vaccines needs to be updated to accommodate non-specific effects. Currently, non-specific effects are not routinely captured in phase I-III clinical trials or in the post-licensure safety surveillance. For instance, an infection with Streptococcus pneumoniae occurring months after a diphtheria-tetanus-pertussis vaccination would not be considered an effect of the vaccination, although evidence indicates it might well be for female individuals. Here, as a starting point for discussion, we propose a new framework that considers the non-specific effects of vaccines in both phase III trials and post-licensure.

Cognitive impairment; Diabetes mellitus; Diabetic retinopathy Discapacidad cognitiva; Diabetes mellitus; Retinopatía diabética Discapacitat cognitiva; Diabetis mellitus; Retinopatia diabètica Background: Retinal neurodegeneration is evident in early diabetic retinopathy (DR) which may be associated with other neurodegenerative diseases like Alzheimer's disease (AD). Objective: To investigate diabetes and DR as a risk marker of present and incident AD. Methods: A register-based cohort study was performed. We included 134,327 persons with diabetes above 60 years of age, who had attended DR screening, and 651,936 age- and gender-matched persons without diabetes. Results: At baseline, the prevalence of AD was 0.7% and 1.3% among patients with and without diabetes, respectively. In a multivariable regression model, patients with diabetes were less likely to have AD at baseline (adjusted OR 0.63, 95% CI 0.59–0.68). During follow-up, incident AD was registered for 1473 (0.35%) and 6,899 (0.34%) persons with and without diabetes, respectively. Compared to persons without diabetes, persons with diabetes and no DR had a lower risk to develop AD (adjusted HR 0.87, 95% CI 0.81–0.93), while persons with diabetes and DR had higher risk of AD (adjusted HR 1.24, 95% CI 1.08–1.43). When persons with diabetes and no DR were used as references, a higher risk of incident AD was observed in persons with DR (adjusted HR 1.34, 95% CI 1.18–1.53). Conclusion: Individuals with diabetes without DR were less likely to develop AD compared to persons without diabetes. However, individuals with DR had a 34% higher risk of incident AD, which raise the question whether screening for cognitive impairment should be done among individuals with DR. This work was supported by VELUX FONDEN (grant number 00028744) and Odense University Hospital PhD Foundation (grant number 4339).

Studies often report beneficial effects of physical exercise on depression symptomatology, both in clinical and community samples. In clinical samples, effects are observed using physical exercise as primary treatment and supplement to antidepressant medications and/or psychotherapies. Magnitudes vary with sample characteristics, exercise measure, and study rigor. Both propensity to exercise and vulnerability to depression show genetic influences, suggesting gene–environment interplay. We investigated this in a Danish Twin Registry-based community sample who completed a cycle fitness test and detailed assessments of depression symptomatology and regular exercise engagement that enabled estimates of typical total, intentional exercise-specific, and other metabolic equivalent (MET) expenditures. All exercise-related measures correlated negatively with depression symptomatology (− .07 to − .19). Genetic variance was lower at higher levels of cycle fitness, with genetic and shared environmental correlations of − .50 and 1.0, respectively. Nonshared environmental variance in depression was lower at higher levels of total MET, with no indications of genetic or environmental covariance. Being physically active and/or fit tended to prevent depression, apparently because fewer participants with higher levels of activity and fitness reported high depression symptomatology. This was driven by nonshared environmental influences on activity but genetic influences on physical fitness. Genetic correlation suggested people less genetically inclined toward physical fitness may also be genetically vulnerable to depression, possibly because inertia impedes activity but also possibly due to social pressures to be fit. Exercise programs for general well-being should emphasize participation, not performance level or fitness. We discuss possible interrelations between fitness aptitude and metabolism.

The Danish Twin Registry (DTR) was established in the 1950s, when twins born from 1870 to 1910 were ascertained, and has since been extended to include twins from birth cohorts until 2009. The DTR currently comprises of more than 175,000 twins from the 140 birth cohorts. This makes the DTR the oldest nationwide twin register and among the largest in the world. The combination of data from several surveys, including biological samples and repeated measurements on the same individuals, and data from Danish national registers provides a unique resource for a wide range of twin studies. This article provides an updated overview of the data in the DTR: First, we provide a summary of the establishment of the register, the different ascertainment methods and the twins included; then follows an overview of major surveys conducted in the DTR since 1994 and a description of the DTR biobank, including a description of the molecular data created so far; finally, a short description is given of the linkage to Danish national registers at Statistics Denmark and some recent examples of studies using the various data resources in the DTR are highlighted.

Pulmonary surfactant protein D (SP-D) is an important component of the pulmonary innate immune system with the ability to dampen cigarette smoke-induced lung inflammation. However, cigarette smoking mediates translocation of SP-D from the lung to the blood, and serum SP-D (sSP-D) has therefore previously been suggested as marker for smoke-induced lung injury. In support of this notion, associations between high sSP-D and low lung function measurements have previously been demonstrated in smokers and in chronic obstructive lung disease (COPD). The present investigations employ a 12-yr longitudinal Danish twin study to test the hypothesis that baseline sSP-D variation has the capacity to identify smokers with normal baseline lung function who are at high risk of significant future smoke-induced lung function decline. We find that sSP-D is significantly increased in those with normal lung function at baseline who develop lung function decline during follow-up compared with those who stay lung healthy. Moreover, we demonstrate that it is the smoke-induced baseline sSP-D level, and not the constitutional level, which has capacity as biomarker, and which is linearly increased with the decline in lung function during follow-up. In conclusion, we here present first observation of increased sSP-D for identification of high-risk smokers.

The field of medical studies is rich in stereotypical conceptions of the practitioners of the various medical specialisations.By means of a Kahoot of 25 questions about practitioners of nine different medical specialisations, we were trying to see, if a group of people from the medical field (n = 20) and a control group of librarians (n = 22) would answer the questions correctly. The questions were jokes about various medical specialisations, and people were supposed to guess, which kind of medical doctor they described.Those with a background in medical studies were faster and more precise than the librarians. Some of the stereotypes described by the jokes, were known to both groups, others were not. The most familiar stereotypes were those describing anaesthesiologists as sleepy and psychiatrists as crazy. It appeared, that many of the medical speciality stereotypes took their point of departure in the idea, that doctors resemble their patients.The survey has limited data, and therefore the conclusion is not very wide-reaching. Some stereotypes were familiar to both groups, others were not. The data indicate that in some cases, contradictory stereotypes exist about individual specialisations.

Purpose: The Danish Excellence Centre in Ophthalmic Epidemiology (DECODE-EYE) is a national research collaboration formed in order to study the real-life interaction between ocular and systemic disease based on the entire Danish population. Here, we aim to describe the study design and the methodology, which will be used. Methods: We will extract data from various healthcare registers and databases including the Danish Civil Registration System (unique personal identifier), the Danish National Patient Register (inpatient and outpatient visits), the Danish National Prescription Registry (redeemed prescription drugs), the National Health Service Register (data on health services in primary health care), the Danish Register of Cause of Death (data on cause of death), Statistics Denmark (demographic and socioeconomic data), the Danish Registry of Diabetic Retinopathy (level of diabetic retinopathy (DR) in diabetes patients) and the database of the Danish Association of the Blind (date and cause of blindness). Relevant registers will be linked by the unique personal identifier, and associations will be examined cross-sectional and/or longitudinally, in principle in 1:5 age- and gender-matched case–control cohort studies. Conclusion: Denmark has a strong tradition in register-based healthcare research, given a high number of validated national registers and databases. DECODE-EYE will provide Danish, large-scale data on associations between ocular and systemic disease. With a target population of 5.8 million individuals, twelve separate studies (Protocols A–L) have initially been designed to be studied in the upcoming years. These will provide novel data on interactions between systemic disease and relevant ophthalmological end-points like blindness, DR, glaucoma, corneal disease, retinal vascular disease, cataract and intravitreal angiostatic treatment.

Highlights • Abnormal structure of thalamic nuclei has been proposed to be a feature of migraine pathophysiology. • We measured volume of thalamic nuclei in 156 migraine patients with aura using two advanced methods. • We found no abnormalities of thalamic volume in migraine with aura., Migraine with aura is a highly prevalent disorder involving transient neurological disturbances associated with migraine headache. While the pathophysiology is incompletely understood, findings from clinical and basic science studies indicate a potential key role of the thalamus in the mechanisms underlying migraine with and without aura. Two recent, clinic-based MRI studies investigated the volumes of individual thalamic nuclei in migraine patients with and without aura using two different data analysis methods. Both studies found differences of thalamic nuclei volumes between patients and healthy controls, but the results of the studies were not consistent. Here, we investigated whether migraine with aura is associated with changes in thalamic volume by analysing MRI data obtained from a large, cross-sectional population-based study which specifically included women with migraine with aura (N = 156), unrelated migraine-free matched controls (N = 126), and migraine aura-free co-twins (N = 29) identified from the Danish Twin Registry. We used two advanced, validated analysis methods to assess the volume of the thalamus and its nuclei; the MAGeT Brain Algorithm and a recently developed FreeSurfer-based method based on a probabilistic atlas of the thalamic nuclei combining ex vivo MRI and histology. These approaches were very similar to the methods used in each of the two previous studies. Between-group comparisons were corrected for potential effects of age, educational level, BMI, smoking, alcohol, and hypertension using a linear mixed model. Further, we used linear mixed models and visual inspection of data to assess relations between migraine aura frequency and thalamic nuclei volumes in patients. In addition, we performed paired t-tests to compare volumes of twin pairs (N = 29) discordant for migraine with aura. None of our analyses showed any between-group differences in volume of the thalamus or of individual thalamic nuclei. Our results indicate that the pathophysiology of migraine with aura does not involve alteration of thalamic volume.

Loos, Ruth J F/0000-0002-8532-5087; Huibregtse, Brooke M./0000-0003-0977-7249; Kandler, Christian/0000-0002-9175-235X; Hjelmborg, Jacob/0000-0001-9630-9149; mangino, massimo/0000-0002-2167-7470; Siribaddana, Sisira/0000-0001-5821-2557; Plomin, Robert/0000-0002-0756-3629; Latvala, Antti/0000-0001-5695-117X; Kaprio, Jaakko/0000-0002-3716-2455; Willemsen, Gonneke/0000-0003-3755-0236; Tan, Qihua/0000-0003-3194-0030; Pahlen, Shandell/0000-0003-0753-4155; Pedersen, Nancy/0000-0001-8057-3543; Haworth, Claire/0000-0002-8608-289X; Nistico, Lorenza/0000-0003-1805-6240; Skytthe, Axel/0000-0002-8629-4913; van Beijsterveldt, Toos/0000-0002-6617-4201; Rebato, Esther/0000-0003-1221-8501; Li, Lintao/0000-0002-0604-9660; Bartels, Meike/0000-0002-9667-7555; Silventoinen, Karri/0000-0003-1759-3079; Cunha Oliveira, Vinicius/0000-0002-8658-3774; Sund, Reijo/0000-0002-6268-8117; Sodemann, Morten/0000-0001-8992-2500; Rasmussen, Finn/0000-0001-7915-7809; Harden, Kathryn/0000-0002-1557-6737; Medda, Emanuela/0000-0003-4837-4549; Kyvik, Kirsten Ohm/0000-0003-2981-0245; Colodro Conde, Lucia/0000-0002-9004-364X WOS: 000517442200060 PubMed: 31364586 The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m(2)) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural-geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status. Academy of FinlandAcademy of Finland [266592, 100499, 205585, 118555, 141054, 265240, 263278, 264146]; Osaka University's International Joint Research Promotion Program; Centre of Research Excellence Grant from the National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1079102]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HD068435, R01 MH062375, 1R01ESO15150-01, R21 AG039572]; National Medical Research Council Research Fellowship; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [1RO1-AG13662-01A2]; Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) [340-2013-5867]; Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation; Swedish Asthma and Allergy Association's Research Foundation; Special Fund for Health Scientific Research in the Public Welfare, China [201502006]; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015, HD10333]; National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation; Research Council for Health and Disease; Velux Foundation; US National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 AG08761]; Fund of Scientific Research, FlandersFWO; ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007 [201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Cancer Research UKCancer Research UK [C1418/A7974]; W T Grant Foundation; University of London Central Research fund; Medical Research CouncilMedical Research Council UK (MRC) [G81/343, G120/635]; Economic and Social Research CouncilEconomic & Social Research Council (ESRC) [RES-000-22-2206]; Institute of Social Psychiatry [06/07-11]; Leverhulme Research FellowshipLeverhulme Trust [RF/2/RFG/2008/0145]; Goldsmiths, University of London; UK Medical Research CouncilMedical Research Council UK (MRC) [MR/M021475/1, G0901245]; National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01AG053217, RC2 HL103416]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81125007]; Global Research Network Program of the National Research Foundation [NRF 2011-220-E00006]; European Research Council (ERC)European Research Council (ERC) [240994]; Michigan State University; National Institute of Mental Health (NIMH)United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01, 1R01-MH118848-01]; Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [R01-HD066040]; MSU Foundation [11-SPG-2518]; Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain [08633/PHCS/08, 15302/PHCS/10, 19479/PI/14]; Ministry of Science and Innovation, SpainSpanish Government [PSI2009-11560, PSI2014-56680-R]; MagW/ZonMW [904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; European Research CouncilEuropean Research Council (ERC) [ERC-230374]; JSPS KAKENHI JP [23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [437015, 607358]; Bonnie Babes Foundation [BBF20704]; Financial Markets Foundation for Children [032-2007]; Victorian Government; Portuguese agency for research (The Foundation for Science and Technology [FCT]) [POCI/DES/56834/2004]; Wellcome TrustWellcome Trust; Medical Research CouncilMedical Research Council UK (MRC); European UnionEuropean Union (EU); National Institute for Health Research (NIHR)National Institute for Health Research (NIHR); King's College London; Fonds Quebecois de la Recherche sur la Societe et la CultureFQRNT; Fonds de la Recherche en Sante du QuebecFonds de la Recherche en Sante du Quebec; Social Science and Humanities Research Council of Canada; National Health Research Development Program; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR); Sainte-Justine Hospital's Research Center; Canada Research Chair ProgramCanada Research Chairs; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1 B00047]; Swedish Research CouncilSwedish Research Council [2017-00641]; UK Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [31/D19086]; MRCMedical Research Council UK (MRC) [MR/M021475/1]; Krkkale University [2009/43]; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH58354]; National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIA R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; VA San Diego Center of Excellence for Stress and Mental Health; Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [15H05105]; Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust; Stockholm County Council (ALF-projects)Stockholm County Council; Twins, a nonprofit Association for Scientific Research in Multiple Births (Belgium); [5T32DA017637]; [5T32AG052371] This study was conducted within the CODATwins project (Academy of Finland #266592). K Silventoinen is supported by Osaka University's International Joint Research Promotion Program. This research was facilitated through access to Twins Research Australia, a national resource supported by a Centre of Research Excellence Grant (ID: 1079102), from the National Health and Medical Research Council. The Boston University Twin Project is funded by grants (#R01 HD068435 #R01 MH062375) from the National Institutes of Health to K. Saudino. Paulo Ferreira is funded by a National Medical Research Council Research Fellowship. California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01).; The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. The CATSS-Study is supported by the Swedish Research Council through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Swedish Heart-Lung Foundation and the Swedish Asthma and Allergy Association's Research Foundation.; Chinese National Twin Registry is funded by Special Fund for Health Scientific Research in the Public Welfare (Project No: 201502006), China. Colorado Twin Registry is funded by NIDA-funded center grant DA011015, & Longitudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637 and 5T32AG052371. Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation and the US National Institute of Health (P01 AG08761). Since its origin, the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a nonprofit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE - European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145 and AA-09203 to R J Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J Kaprio). Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Waves 1-3 of Genesis 12-19 were funded by the W T Grant Foundation, the University of London Central Research fund and a Medical Research Council Training Fellowship (G81/343) and Career Development Award (G120/635) to Thalia C. Eley. Wave 4 was supported by grants from the Economic and Social Research Council (RES-000-22-2206) and the Institute of Social Psychiatry (06/07-11) to Alice M. Gregory, who was also supported at that time by a Leverhulme Research Fellowship (RF/2/RFG/2008/0145). Wave 5 was supported by funding to Alice M. Gregory from Goldsmiths, University of London. T. C. Eley is partly funded by a program grant from the UK Medical Research Council (MR/M021475/1).; This study presents independent research [partly] funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The Minnesota Twin Registry (MTR) acknowledges support from NIH grant R01AG053217. Guangzhou Twin Eye Study is supported by National Natural Science Foundation of China (grant #81125007). Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 and 1R01-MH118848-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) and 11-SPG-2518 from the MSU Foundation. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD or the National Institutes of Health. The Murcia Twin Registry is supported by Fundacion Seneca, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08, 15302/PHCS/10 & 19479/PI/14) and Ministry of Science and Innovation, Spain (PSI2009-11560 & PSI2014-56680-R). The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO+); the European Research Council (ERC-230374), the Avera Institute, Sioux Falls, South Dakota (USA). Osaka University Aged Twin Registry is supported by grants from JSPS KAKENHI JP (23593419, 24792601, 26671010, 24590695, 26293128, 16K15385, 16K15978, 16K15989, 16H03261). PETS was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to JC, and RS), the Bonnie Babes Foundation (grant number BBF20704 to JMC), the Financial Markets Foundation for Children (grant no. 032-2007 to JMC), and by the Victorian Government's Operational Infrastructure Support Program.; Madeira data comes from the following project: Genetic and environmental influences on physical activity, fitness and health: the Madeira family study Project reference: POCI/DES/56834/2004 Founded by the Portuguese agency for research (The Foundation for Science and Technology [FCT]). TwinsUK receives funding from the Wellcome Trust, Medical Research Council and European Union.; TwinsUK and M. Mangino are supported by the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (Michel Boivin). South Korea Twin Registry is supported by National Research Foundation of Korea (NRF-371-2011-1 B00047). We acknowledge The Swedish Twin Registry for access to data. The Swedish Twin Registry is managed by Karolinska Institutet and receives funding through the Swedish Research Council under the grant no. 2017-00641.; The Twins Early Development Study (TEDS) is supported by a program grant (G0901245) from the UK Medical Research Council and the work on obesity in TEDS is supported in part by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). Currently TEDS is supported by MRC grant 'MR/M021475/1'. The Texas Twin Project is currently funded by grant R01HD083613 from the National Institutes of Health. S. Y. oncel and F. Aliev are supported by Krkkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117. The University of Southern California Twin Study is funded by a grant from the National Institute of Mental Health (R01 MH58354). Washington State Twin Registry (formerly the University of Washington Twin Registry) was supported in part by grant NIH RC2 HL103416 (D. Buchwald, PI). Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381 and R01 AG022982, and, in part, with resources of the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) (grant number 15H05105) from the Japan Society for the Promotion of Science.

AIMS: This study aimed at quantifying the healthy donor effect by comparing self-perceived mental and physical health between blood donors and non-donors.BACKGROUND: In theory, the selection process known as the healthy donor effect should result in better self-perceived, health-related quality of life in donors than in non-donors.METHODS: The Short Form-12 data from the Danish Twin Registry (DTR) was compared with the data from the Danish Blood Donor Study (DBDS). Data on age, sex and smoking status were included in the analyses. The multivariable linear regression analysis was stratified by sex and age group intervals. Outcome variables were the mental component score (MCS) and the physical component score (PCS).RESULTS: A total of 28 982 and 36 913 participants from the DTR and the DBDS, respectively, were included in this study. Younger donors had higher MCS than non-donors, whereas MCS was only marginally high in older donors compared with non-donors. In contrast, PCS was almost similar for both young donors and non-donors. With the increase in age, non-donors had lower PCS than donors.CONCLUSIONS: Two selection patterns were revealed. Among young individuals, better self-perceived mental health was associated with a blood donor. With the increase in age, better self-perceived physical health was associated with blood donation.

Background: Optic neuritis (ON) is often associated with multiple sclerosis (MS). Early diagnosis is critical to optimal patient management. Objective: To estimate the incidence of acute ON and the rates of conversion to MS and antibody-mediated ON. Method: Population-based prospective study was performed in patients with ON from three ophthalmological departments and 44 practicing ophthalmologists from 2014 to 2016. Ophthalmological and neurological examination, magnetic resonance imaging (MRI), determination of aquaporin-4(AQP4)-IgG and myelin-oligodendrocyte glycoprotein (MOG)-IgG were investigated blindly. Results: In all, 63 patients were evaluated and 51 fulfilled the criteria for ON. All were Caucasian, with female:male ratio of 2.2:1 and a median age of 38 years (16–66); 44 (86%) had a single episode of ON (four bilateral), while 7/51 (14%) had recurrent ON. The overall age-specific incidence was 3.28 (2.44–4.31) per 100,000 person years, 2.02 for men and 4.57 for women. At follow-up, 20 patients met the diagnostic criteria for MS, MRI lesions disseminated in space and time in 17/20 patients. AQP4-IgG was detected in none, MOG-IgG was detected in two patients. Conclusion: The prospective incidence of ON was estimated. MRI enabled a diagnosis of MS in a subgroup of patients. Antibody-mediated ON with specificity for MOG was detected in 4% of cases.

Background Biochemical markers of bone turnover are lower in patients with type 2 diabetes, which may be explained by genetic variants being associated with type 2 diabetes and bone turnover as well as environmental factors. We hypothesized that bone turnover markers associate with and predict changes in glucose homeostasis after control for genetics and shared environment. Methods 1071 healthy, non-diabetic (at baseline, 1997–2000) adult mono- and dizygotic twins participating in the prospective study GEMINAKAR were reassessed between 2010 and 2012 with clinical evaluation, biochemical tests and oral glucose tolerance test. Fasting bone turnover markers (CTX, P1NP and osteocalcin) were measured. The association between bone turnover, glucose homeostasis and the ability of bone turnover markers to predict changes in glucose homeostasis were assessed in cross-sectional and longitudinal analyses. Analyses were performed both at an individual level and adjusted for shared environmental and genetic factors. Results Glucose levels increased with age, and 33 (3%) participants had developed type 2 diabetes at follow-up. In women, bone turnover markers increased with age, whereas for men only osteocalcin increased with age. Bone turnover markers were not associated with fasting glucose, insulin, or HOMA-IR at baseline or follow-up before or after adjustment for age, sex, BMI, smoking, and use of medication at baseline. Variation in bone turnover markers was mainly explained by unique environmental factors, 70%, 70% and 55% for CTX, P1NP and osteocalcin, respectively, whereas additive genetic factors explained 7%, 13% and 45% of the variation in CTX, P1NP and osteocalcin. Conclusions Bone turnover markers were not associated with baseline plasma glucose levels and did not predict changes in glucose homeostasis. Variation in bone turnover markers is mainly explained by environmental factors, however, compared to CTX and P1NP, genetic factors have a larger impact on osteocalcin levels.

Objective: To assess the incidence of chronic persistent rheumatoid arthritis (RA) in a population based cohort of twins and to determine the impact of smoking. Methods: In a historical cohort study on twins born 1920 to 1982 we identified 157 cases of RA among 45,280 responders (response rate 80%). Information on smoking was obtained by questionnaire and interview. A mixed effect Poisson regression model was used to estimate incidence rate ratios with age, sex, smoking duration and smoking intensity as covariates. We used the SplitLexis procedure in the Epi R package to study a possible effect of period or cohort in addition to age on the variation of the incidence. Results: The annual incidence of chronic persistent RA was 18.8 per 100,000 person years aged 15-73 years (females 25.2, males 12.0), increasing with age to a maximum at sixty years in females and seventy years in males. The incidence rate ratio among ever smoking patients was 1.96 (95% CI: 1.43 – 3.76), 1.93 (95% CI: 1.00 – 3.7) after 30 pack-years, and 1.034 (p

Study design Clinical, radiological, and genetic determination of zygosity of twin pairs from the Danish Twin Registry who self-reported having adolescent idiopathic scoliosis (AIS). Objective To establish concordance rates of AIS. Summary of background data The etiology of and the true mode of inheritance of AIS remain unclear. Studies on concordance in twin pairs provide a basis for analyzing the influence of genetic versus environmental factors. In 2007, using self-report of AIS from the Danish Twin Registry, concordance rates of 0.13 in monozygotic twins and 0.00 in dizygotic twins were reported. Methods All 46,418 twins registered in the Danish Twin Registry born from 1931 to 1982 were sent a survey, which included questions about scoliosis. The survey was returned by 34,944 individuals (75.3%) representing 23,204 pairs. From the present study, 548 individuals representing 274 complete twin pairs in which at least one twin self-reported having scoliosis were invited to a clinical and radiological examination. Zygosity was established by genetic testing. Results A total of 182 individuals (33.2%) of the original cohort agreed to participate, 128 of whom had scoliosis by self-report. There were 91 twin pairs, in which one or both twins had reported scoliosis and 36 individuals whose twin did not want to participate. Only 35 (27%) of the 128 participants with self-reported scoliosis had a clinically and radiologically confirmed curve. Calculating concordance in twins with Cobb angles greater than 10°, we found that the pairwise concordance rate was 0.4 (0.10-0.70) for monozygotic and 0.05 (-0.05-0.15) for dizygotic twins, P = 0.05, probandwise concordance was 0.45 (0.16-0.74) for monozygotic and 0.1 (-0.03-0.23) for dizygotic pairs. Conclusion Concordance rates in a Danish twin population using genetic testing for zygosity are higher than previously reported using self-report. Although not statistically significant, the differences in monozygotic and dizygotic pairs indicate that genetic factors may be of importance for scoliosis. Level of evidence 3.

Epidemiological studies of the uncommon disorder neuromyelitis optica spectrum disorder (NMOSD) may be difficult to interpret because of the evolving nature of diagnostic criteria, differences in the definition and accuracy of NMOSD diagnosis, the completeness of case ascertainment, and variability in assays for the disease‐specific biomarker aquaporin‐4 (AQP4)‐IgG. A sub‐group of patients with the clinical syndrome NMOSD lack detectable AQP4‐IgG and in these cases an accurate diagnosis requires precise diagnostic algorithms and longitudinal follow‐up. Consecutive sets of criteria for NMO/NMOSD have been introduced during the two last decades. Such criteria need validation in different populations. Detection of other autoantibodies, such as IgG specific for myelin oligodendrocyte glycoprotein or for glial fibrillary acidic protein in a sub‐group of AQP4‐IgG–negative NMOSD patients, has improved over the past decade and may lead to overlap of the clinical syndromes/phenotypes. This review begins by summarizing current knowledge on the widening clinical spectrum of NMOSD. Subsequently, we describe two epidemiological studies from Denmark carried out in two different decades (1998–2008 and 2007–2014) and comment on the differences in study design, patient ascertainment, and interpretation of results. These factors may explain some of the observed differences, reflecting the complexity and providing a clear example of this development.

Objectives: The overall distribution of disease courses in multiple sclerosis (MS) is well established, but little is known about the distribution among familial MS cases. We examine the frequency of the different MS courses among familial and sporadic MS cases and determine whether MS cases within the same family had the same age at diagnosis and have experienced the same disease course. Materials and methods: This is a nationwide register study, based on data from the Danish MS Registry, the Danish Civil Registration System, and the Danish National Patient Registry. The main variables are MS diagnosis, MS course, and first-degree relatives with MS The statistical analyses were carried out using logistic regression analysis, Kappa coefficient, and intraclass correlations coefficient. Results: In total, 7402 MS cases were included in the study, of which 531 have an affected first-degree relatives, and 6871 are sporadic. We found that relapsing-remitting MS including secondary progressive MS was more common among familial MS cases than among sporadic MS cases (Odds ratio = 1.64, 95% CI: 1.20-2.24, P = 0.002). We subsequently analyzed data on 133 MS families and found that MS courses correlate between the first and the second MS case diagnosed, while age at diagnosis does not. Conclusion: Familial MS cases are more likely to have relapsing-remitting MS than a progressive course compared to sporadic MS cases. Secondly, we find that within MS families, first-degree relatives are likely to have the same MS course, but we do not find that they are diagnosed at the same age.

Background The diagnosis of multiple sclerosis (MS) is still complicated despite improvement in diagnostic guidelines. This means that time from first symptom to diagnosis in some cases is prolonged. Many aspects of MS aetiology are unknown, but the involvement of a genetic component is well established. This is also highlighted by the occurrence of familial MS cases, which represent 10–20% of all MS cases. We hypothesize that subsequent family members in a MS family, have a shorter time from onset of disease to diagnosis compared to sporadic MS cases. To investigate this, we have conducted a register study comparing time from onset to diagnosis in familial and sporadic MS cases. Methods This is a nationwide register study based on information from the Danish Multiple Sclerosis Registry and the Danish Civil Registration System. We included familial (first-degree relatives) and sporadic MS cases and calculated time lag between onset and diagnosis of MS for sporadic MS cases and for1st, 2nd and 3rd family members within the MS families. Median test and Cox regression were the statistical methods used to compare the familial and sporadic groups. Results We found that 2nd and 3rd affected family member had a significant shorter time from first symptom to diagnosis compared to sporadic MS cases (2nd family member: Hazard Ratio (HR): 1.12, CI: 1.03–1.21, p = 0.007 adjusted: HR: 0.95 p = 0.22, CI 0.89-1-03 and 3rd family member HR: 1.64 CI: 1.22–2.20, p = 0.001 adjusted model: HR: 1.70, p-value: 0.000, CI: 1.32–2.18). The same difference was not seen between 1st family members and sporadic cases (HR: 1.05, CI: 0.98–1.13, p = 0.15, adjusted: 0.98, p-value: 0.53, CI: 0.91–1.05). Estimated marginal mean delay in the four groups were 4.60 years (95% CI: 4.11–5.01) in1st family members, 4.23 years (3.71–4.75) in 2nd family members, 2.11 years (0.95–3.26) in 3rd family members and 4.99 years (4.99–4.99) in sporadic MS cases. Conclusion The 2nd and 3rd family members in MS families tend do get diagnosed faster than sporadic cases. This has implications in the diagnostic process of familial MS cases.

Objectives: Surfactant protein-D (SP-D), an innate immune defence molecule of the collectin family, is expressed in lungs and additional extrapulmonary epithelia. SP-D has immune modulatory and anti-microbial effects depending on its oligomerization. The ratio of high molecular weight (HMW): low molecular weight (LMW) SP-D in serum is mainly determined by the Met11Thr polymorphism (SNP rs721917). We aimed to study the SP-D serum level and the molecular size distribution in patients with untreated axial spondyloarthritis (axSpA) as compared with control subjects.Methods: Thirty-four patients with disease modifier untreated axSpA according to the ASAS criteria, age 19-63 years, disease duration 3.9 (2.2-5.6) years were included. Demographics, smoking habits, HLA-B27 status, ASDAS, BASDAI, BASFI, BASMI and visual analogue scale scores were recorded. SP-D in serum was measured by ELISA. DNA was isolated from whole blood and single nucleotide polymorphism rs721917 was genotyped. SP-D molecular size distribution was determined using gel filtration chromatography.Results: SP-D in serum did not differ between patients with axSpA and healthy controls, 1177 (869, 1536) vs 910 (494, 1682) (P = 0.35) and SP-D did not correlate with disease activity. However, the HMW/LMW ratio of SP-D in serum was significantly lower in axSpA, 0.38 (0.18, 0.53) compared with controls 1.49 (0.37, 3.24) when adjusting for the Met11Thr polymorphism, gender, age, BMI and smoking (P = 0.0004). There was no correlation between HMW/LMW ratio and CRP or composite diseases outcome measures.Conclusion: We suggest that predominance of LMW oligomeric variants of SP-D may enhance local or systemic inflammatory responses in axSpA.

Objectives This study was designed to examine the association between loss-of-function mutations in the filaggrin gene (FLG) and atopic dermatitis (AD) and asthma in adult twins. Methods A previously well-characterized cohort of 575 adult twins were genotyped for the loss-of-function mutations in FLG (R501X, 2282del4 and R2447X) most common among northern Europeans. Subjects were examined for symptoms of atopic diseases as well as for lung function, airway responsiveness, and atopy. Results In the whole population of twins, the risk for AD was significantly increased in individuals with FLG mutations in comparison with wild-type carriers (34.3% vs. 21.8%) after adjustment for possible confounders (odds ratio [OR] 1.92, 95% confidence interval [CI] 1.07–3.41; P = 0.028). A significant association was also observed for persistent AD (OR 2.10, 95% CI 1.02–4.36; P = 0.046). There were no significant differences in risk for asthma by FLG mutation status in individuals with and without AD, respectively (P-value for interaction, 0.595). In 11 dizygotic twin pairs discordant for FLG mutation status, risk for AD was higher in the twin carrying the FLG mutation (five of 11 [45.5%] twins had developed AD) than in the non-carrier co-twin (two of 11 [18.2%] twins had developed AD) (OR 2.50, 95% CI 0.45–13.85; P = 0.293). FLG status did not explain a significant proportion of the variation in AD (P = 0.328) or asthma (P = 0.321). Conclusions Filaggrin gene mutations are risk factors for the presence and persistence of AD and explain the discordance of AD within dizygotic twin pairs.

AIMS/HYPOTHESIS: A number of studies have shown that leucocyte telomere length (LTL) is inversely associated with insulin resistance and type 2 diabetes mellitus. The aim of the present longitudinal cohort study, utilising a twin design, was to assess whether shorter LTL predicts insulin resistance or is a consequence thereof. METHODS: Participants were recruited between 1997 and 2000 through the population-based national Danish Twin Registry to participate in the GEMINAKAR study, a longitudinal evaluation of metabolic disorders and cardiovascular risk factors. Baseline and follow-up measurements of LTL and insulin resistance over an average of 12 years were performed in a subset of the Registry consisting of 338 (184 monozygotic and 154 dizygotic) same-sex twin pairs. RESULTS: Age at baseline examination was 37.4 ± 9.6 (mean ± SD) years. Baseline insulin resistance was not associated with age-dependent changes in LTL (attrition) over the follow-up period, whereas baseline LTL was associated with changes in insulin resistance during this period. The shorter the LTL at baseline, the more pronounced was the increase in insulin resistance over the follow-up period (p AIMS/HYPOTHESIS: A number of studies have shown that leucocyte telomere length (LTL) is inversely associated with insulin resistance and type 2 diabetes mellitus. The aim of the present longitudinal cohort study, utilising a twin design, was to assess whether shorter LTL predicts insulin resistance or is a consequence thereof.METHODS: Participants were recruited between 1997 and 2000 through the population-based national Danish Twin Registry to participate in the GEMINAKAR study, a longitudinal evaluation of metabolic disorders and cardiovascular risk factors. Baseline and follow-up measurements of LTL and insulin resistance over an average of 12 years were performed in a subset of the Registry consisting of 338 (184 monozygotic and 154 dizygotic) same-sex twin pairs.RESULTS: Age at baseline examination was 37.4 ± 9.6 (mean ± SD) years. Baseline insulin resistance was not associated with age-dependent changes in LTL (attrition) over the follow-up period, whereas baseline LTL was associated with changes in insulin resistance during this period. The shorter the LTL at baseline, the more pronounced was the increase in insulin resistance over the follow-up period (p CONCLUSIONS/INTERPRETATION: These findings suggest that individuals with short LTL are more likely to develop insulin resistance later in life. By contrast, presence of insulin resistance does not accelerate LTL attrition.

Migraine with aura is considered a putative risk factor for silent brain infarcts and white matter hyperintensities in women. In an MRI study of Danish female twins aged 30–60 years, Gaist et al. compare 172 affected women with 139 controls, but find no evidence to support the proposed associations., A small number of population-based studies reported an association between migraine with aura and risk of silent brain infarcts and white matter hyperintensities in females. We investigated these relations in a population-based sample of female twins. We contacted female twins ages 30–60 years identified through the population-based Danish Twin Registry. Based on questionnaire responses, twins were invited to participate in a telephone-based interview conducted by physicians. Headache diagnoses were established according to the International Headache Society criteria. Cases with migraine with aura, their co-twins, and unrelated migraine-free twins (controls) were invited to a brain magnetic resonance imaging scan performed at a single centre. Brain scans were assessed for the presence of infarcts, and white matter hyperintensities (visual rating scales and volumetric analyses) blinded to headache diagnoses. Comparisons were based on 172 cases, 34 co-twins, and 139 control subjects. Compared with control subjects, cases did not differ with regard to frequency of silent brain infarcts (four cases versus one control), periventricular white matter hyperintensity scores [adjusted mean difference (95% confidence interval): −0.1 (−0.5 to 0.2)] or deep white matter hyperintensity scores [adjusted mean difference (95% confidence interval): 0.1 (−0.8 to 1.1)] assessed by Scheltens’ scale. Cases had a slightly higher total white matter hyperintensity volume compared with controls [adjusted mean difference (95% confidence interval): 0.17 (−0.08 to 0.41) cm 3 ] and a similar difference was present in analyses restricted to twin pairs discordant for migraine with aura [adjusted mean difference 0.21 (−0.20 to 0.63)], but these differences did not reach statistical significance. We found no evidence of an association between silent brain infarcts, white matter hyperintensities, and migraine with aura.

Kandler, Christian/0000-0002-9175-235X; Bartels, Meike/0000-0002-9667-7555; Medland, Sarah E/0000-0003-1382-380X; Kaprio, Jaakko/0000-0002-3716-2455; Fagnani, Corrado/0000-0001-5771-7772; de Freitas, Duarte Luis/0000-0001-6642-3370; Hjelmborg, Jacob/0000-0001-9630-9149; mangino, massimo/0000-0002-2167-7470; Busjahn, Andreas/0000-0001-9650-6919; Montgomery, Grant W/0000-0002-4140-8139; Moller, Soren/0000-0003-0858-4269; Heikkila, Kauko/0000-0002-9256-8028; Skytthe, Axel E/0000-0002-8629-4913; Christensen, Kaare/0000-0002-5429-5292; Knafo-Noam, Ariel/0000-0003-0613-1960; ONCEL, Sevgi YURT/0000-0002-0990-292X; Sund, Reijo/0000-0002-6268-8117; Aliev, Fazil/0000-0001-8357-4699; Magnusson, Patrik/0000-0002-7315-7899; Huibregtse, Brooke M./0000-0003-0977-7249; Loos, Ruth J F/0000-0002-8532-5087; Boivin, Michel/0000-0001-8621-9844; Kyvik, Kirsten Ohm/0000-0003-2981-0245; Pahlen, Shandell/0000-0003-0753-4155; van Beijsterveldt, Toos/0000-0002-6617-4201; McAdams, Tom/0000-0002-6825-3499; Sodemann, Morten/0000-0001-8992-2500; Pedersen, Nancy/0000-0001-8057-3543; Derom, Catherine/0000-0001-5574-796X; Plomin, Robert/0000-0002-0756-3629; Rebato, Esther/0000-0003-1221-8501; Saffery, Richard/0000-0002-9510-4181; Harden, Kathryn/0000-0002-1557-6737; Willemsen, Gonneke/0000-0003-3755-0236; Aaltonen, Sari/0000-0002-2873-4263; Silventoinen, Karri/0000-0003-1759-3079; Rasmussen, Finn/0000-0001-7915-7809; Haworth, Claire/0000-0002-8608-289X; Llewellyn, Clare/0000-0002-0066-2827 WOS: 000381870200017 PubMed: 27413137 Background: Both genetic and environmental factors are known to affect body mass index (BMI), but detailed understanding of how their effects differ during childhood and adolescence is lacking. Objectives: We analyzed the genetic and environmental contributions to BMI variation from infancy to early adulthood and the ways they differ by sex and geographic regions representing high (North America and Australia), moderate (Europe), and low levels (East Asia) of obesogenic environments. Design: Data were available for 87,782 complete twin pairs from 0.5 to 19.5 y of age from 45 cohorts. Analyses were based on 383,092 BMI measurements. Variation in BMI was decomposed into genetic and environmental components through genetic structural equation modeling. Results: The variance of BMI increased from 5 y of age along with increasing mean BMI. The proportion of BMI variation explained by additive genetic factors was lowest at 4 y of age in boys (a(2) = 0.42) and girls (a(2) = 0.41) and then generally increased to 0.75 in both sexes at 19 y of age. This was because of a stronger influence of environmental factors shared by co-twins in midchildhood. After 15 y of age, the effect of shared environment was not observed. The sex-specific expression of genetic factors was seen in infancy but was most prominent at 13 y of age and older. The variance of BMI was highest in North America and Australia and lowest in East Asia, but the relative proportion of genetic variation to total variation remained roughly similar across different regions. Conclusions: Environmental factors shared by co-twins affect BMI in childhood, but little evidence for their contribution was found in late adolescence. Our results suggest that genetic factors play a major role in the variation of BMI in adolescence among populations of different ethnicities exposed to different environmental factors related to obesity. CODATwins project (Academy of Finland) [266592]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HD068435, R01 MH062375, 1R01ESO15150-01, HD081437, AA023322, RC2 HL103416]; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; Special Fund for Health Scientific Research in the Public Welfare, China [201502006]; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015, HD10333]; National Program for Research Infrastructure from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease; Velux Foundation; US NIH grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 AG08761]; Fund of Scientific Research, Flanders and Twins, a nonprofit Association for Scientific Research in Multiple Births (Belgium); ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4 [201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease Genetics grantAcademy of Finland [213506, 129680]; Academy of Finland grantAcademy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 264146]; Osaka University's International Joint Research Promotion Program; Cancer Research UKCancer Research UK [C1418/A7974]; W T Grant Foundation; University of London Central Research fund; Medical Research CouncilMedical Research Council UK (MRC) [G81/343, G120/635]; Economic and Social Research CouncilEconomic & Social Research Council (ESRC) [RES-000-22-2206]; Institute of Social Psychiatry [06/07-11]; Leverhulme Research Fellowship grant [RF/2/RFG/2008/0145]; Goldsmiths, University of London, United Kingdom; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81125007]; Medexpert Ltd., Budapest, Hungary; European Research CouncilEuropean Research Council (ERC) [240994, 230374]; Michigan State University; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01]; Eunice Kennedy Shriver National Institute for Child Health and Human DevelopmentUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) [R01-HD066040]; MSU Foundation [11-SPG-2518]; NIH grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21 AG039572]; MagW/ZonMW grant [904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464- 14192]; VU University's Institute for Health and Care Research; Avera Institute, Sioux Falls, SD; Australian National Health and Medical Research Council grantNational Health and Medical Research Council of Australia [437015, 607358]; Bonnie Babes Foundation [BBF20704]; Financial Markets Foundation for Children grant [032-2007]; Victorian Government's Operational Infrastructure Support Program; Portuguese agency for research (The Foundation for Science and Technology) [POCI/DES/56834/2004]; Fonds Quebecois de la Recherche sur la Societe et la CultureFQRNT; Fonds de la Recherche en Sante du QuebecFonds de la Recherche en Sante du Quebec; Social Science and Humanities Research Council of Canada; National Health Research Development Program; Canadian Institutes for Health ResearchCanadian Institutes of Health Research (CIHR); Sainte-Justine Hospital's Research Center; Canada Research Chair ProgramCanada Research Chairs; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1 B00047]; UK Medical Research CouncilMedical Research Council UK (MRC) [G0901245]; UK Biotechnology and Biological Sciences Research Council grant [31/D19086]; Kirikkale University Research grantKirikkale University [KKU 2009/43]; TUBITAK grantTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; European CommunityEuropean Community (EC); National Institute for Health Research BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, United Kingdom; National Institute of Mental Health grantUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH58354]; Japan Society for the Promotion of ScienceMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT)Japan Society for the Promotion of Science [15H05105]; [5T32DA017637-11]; Medical Research CouncilMedical Research Council UK (MRC) [G0901245]; NNF Center for Basic Metabolic ResearchNovo Nordisk Foundation [Metabolic Genetics]; Novo Nordisk FondenNovo NordiskNovo Nordisk Foundation [NNF10CC1016515] This study was conducted within the CODATwins project (Academy of Finland #266592). Support for participating twin projects: The Boston University Twin Project is funded by grants R01 HD068435 and R01 MH062375 from the NIH to KS. California Twin Program was supported by The California Tobacco-Related Disease Research Program grants 7RT-0134H, 8RT-0107H, and 6RT-0354H and by NIH grant 1R01ESO15150-01. Chinese National Twin Registry is funded by Special Fund for Health Scientific Research in the Public Welfare (Project No: 201502006), China. Colorado Twin Registry is funded by NIDA funded center grant DA011015, and Longitudinal Twin Study HD10333; BMH is supported by to 5T32DA017637-11. Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation and the US NIH grant P01 AG08761. Since its origin the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a nonprofit Association for Scientific Research in Multiple Births (Belgium). Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement 201413; National Institute of Alcohol Abuse and Alcoholism grants AA-12502, AA-00145, and AA-09203 to RJR; the Academy of Finland Center of Excellence in Complex Disease Genetics grants 213506 and 129680; and the Academy of Finland grants 100499, 205585, 118555, 141054, 265240, 263278, and 264146 to JK. KS is supported by Osaka University's International Joint Research Promotion Program. Gemini was supported by a grant from Cancer Research UK (C1418/A7974). Waves 1-3 of Genesis 12-19 were funded by the W T Grant Foundation, the University of London Central Research fund and Medical Research Council Training Fellowship grant G81/343 and Career Development Award G120/635 to TCE. Wave 4 was supported by the Economic and Social Research Council grant RES-000-22-2206 and the Institute of Social Psychiatry (06/07-11) to AMG, who was also supported at that time by a Leverhulme Research Fellowship grant RF/2/RFG/2008/0145. Wave 5 was supported by funding to AMG from Goldsmiths, University of London, United Kingdom. Guangzhou Twin Eye Study is supported by National Natural Science Foundation of China grant 81125007. Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. Longitudinal Israeli Study of Twins was funded by the Starting Grant 240994 from the European Research Council to AK. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, and R03-MH63851-01 from the National Institute of Mental Health, R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, and 11-SPG-2518 from the MSU Foundation. The NAS-NRC Twin Registry acknowledges financial support from NIH grant R21 AG039572. Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, and 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464- 14192; VU University's Institute for Health and Care Research; the European Research Council grant 230374; and the Avera Institute, Sioux Falls, SD.; PETS was supported by the Australian National Health and Medical Research Council grant 437015 and 607358 to JC and RS, the Bonnie Babes Foundation grant BBF20704 to JMC, the Financial Markets Foundation for Children grant 032-2007 to JMC, and by the Victorian Government's Operational Infrastructure Support Program. Madeira data comes from the following project: Genetic and environmental influences on physical activity, fitness and health: the Madeira family study Project reference: POCI/DES/56834/2004 Founded by the Portuguese agency for research (The Foundation for Science and Technology). The Quebec Newborn Twin Study acknowledges financial support from the Fonds Quebecois de la Recherche sur la Societe et la Culture, the Fonds de la Recherche en Sante du Quebec, the Social Science and Humanities Research Council of Canada, the National Health Research Development Program, the Canadian Institutes for Health Research, Sainte-Justine Hospital's Research Center, and the Canada Research Chair Program (MB). South Korea Twin Registry is supported by National Research Foundation of Korea grant NRF-371-2011-1 B00047. The Texas Twin Project is currently funded by grants AA023322 and HD081437 from the NIH. The Twins Early Development Study is supported by program grant G0901245 from the UK Medical Research Council and the work on obesity in the Twins Early Development Study is supported in part by the UK Biotechnology and Biological Sciences Research Council grant 31/D19086. SYO and FA are supported by Kirikkale University Research grant KKU 2009/43 and TUBITAK grant 114C117. TwinsUK was funded by European Community's Seventh Framework Programme grant FP7/2007-2013. The study also receives support from the National Institute for Health Research BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London, United Kingdom. The University of Southern California Twin Study is funded by the National Institute of Mental Health grant R01 MH58354. University of Washington Twin Registry was supported in part by grant NIH RC2 HL103416 (D and PI). The West Japan Twins and Higher Order Multiple Births Registry was supported by Grant-in-Aid for Scientific Research (B) grant 15H05105 from the Japan Society for the Promotion of Science.

Until recent years it was believed that migraine with aura was a disorder causing intermittent neurological symptoms, with no impact on brain structure. However, recent MRI studies have reported increased cortical thickness of visual and somatosensory areas in patients with migraine with aura, suggesting that such structural alterations were either due to increased neuronal density in the areas involved, or a result of multiple episodes of cortical spreading depression as part of aura attacks. Subsequent studies have yielded conflicting results, possibly due to methodological reasons, e.g. small number of subjects. In this cross-sectional study, we recruited females aged 30-60 years from the nationwide Danish Twin Registry. Brain MRI of females with migraine with aura (patients), their co-twins, and unrelated migraine-free twins (controls) were performed at a single centre and assessed for cortical thickness in predefined cortical areas (V1, V2, V3A, MT, somatosensory cortex), blinded to headache diagnoses. The difference in cortical thickness between patients and controls adjusted for age, and other potential confounders was assessed. Comparisons of twin pairs discordant for migraine with aura were also performed. Comparisons were based on 166 patients, 30 co-twins, and 137 controls. Compared with controls, patients had a thicker cortex in areas V2 [adjusted mean difference 0.032 mm (95% confidence interval 0.003 to 0.061), V3A [adjusted mean difference 0.037 mm (95% confidence interval 0.008 to 0.067)], while differences in the remaining areas examined were not statistically significant [adjusted mean difference (95% confidence interval): V1 0.022 (-0.007 to 0.052); MT: 0.018 (-0.011 to 0.047); somatosensory cortex: 0.020 (-0.009 to 0.049)]. We found no association between the regions of interest and active migraine, or number of lifetime aura attacks. Migraine with aura discordant twin pairs (n = 30) only differed in mean thickness of V2 (0.039 mm, 95% CI 0.005 to 0.074). In conclusion, females with migraine with aura have a thicker cortex corresponding to visual areas and our results indicate this may be an inherent trait rather than a result of repeated aura attacks.

BACKGROUND Voluntary blood donation is believed to be mostly motivated by altruism. Because studies have suggested that altruistic personality is determined by both genetic and environmental factors, we speculated that willingness to donate blood could also be governed by constitutional factors. This hypothesis was tested in a study among Danish twins. STUDY DESIGN AND METHODS The nationwide Danish Twin Register, which is virtually complete for all twins born since 1968, was linked with Danish portion of the Scandinavian Donation and Transfusion (SCANDAT) Database, which includes information on all active Danish blood donors from 2002 to 2012, to establish blood donor status for Danish twins, who at age 17 years became eligible for donation in 2002 or later. Casewise concordance in monozygotic (MZ) and dizygotic (DZ) twins were presented and heritability was estimated in Mx by variance component analysis in a liability threshold model. RESULTS A total of 274 MZ and 484 same-sex DZ twins age 17 to 27 years were identified as donors in SCANDAT. There was no difference between MZ and DZ twins with regard to age at first donation or number of donations. Casewise concordance rates were 0.61 (95% confidence interval [CI], 0.56-0.67) and 0.41 (95% CI, 0.36-0.47) in MZ and DZ twin pairs, respectively. Heritability analysis using the ACE model found that additive genetic and shared environmental effects accounted for 0.53 (95% CI, 0.33-0.73) and 0.28 (95% CI, 0.10-0.45) of the variance in the motivation to donate blood, respectively. CONCLUSION Becoming a volunteer blood donor is determined by both genetic and environmental factors shared within families.

BACKGROUND: Leucocyte telomere length (LTL) is a complex trait associated with ageing and longevity. LTL dynamics are defined by LTL and its age-dependent attrition. Strong, but indirect evidence suggests that LTL at birth and its attrition during childhood largely explains interindividual LTL variation among adults. A number of studies have estimated the heritability of LTL, but none has assessed the heritability of age-dependent LTL attrition.METHODS: We examined the heritability of LTL dynamics based on a longitudinal evaluation (an average follow-up of 12 years) in 355 monozygotic and 297 dizygotic same-sex twins (aged 19-64 years at baseline).RESULTS: Heritability of LTL at baseline was estimated at 64% (95% CI 39% to 83%) with 22% (95% CI 6% to 49%) of shared environmental effects. Heritability of age-dependent LTL attrition rate was estimated at 28% (95% CI 16% to 44%). Individually unique environmental factors, estimated at 72% (95% CI 56% to 84%) affected LTL attrition rate with no indication of shared environmental effects.CONCLUSIONS: This is the first study that estimated heritability of LTL and also its age-dependent attrition. As LTL attrition is much slower in adults than in children and given that having a long or a short LTL is largely determined before adulthood, our findings suggest that heritability and early life environment are the main determinants of LTL throughout the human life course. Thus, insights into factors that influence LTL at birth and its dynamics during childhood are crucial for understanding the role of telomere genetics in human ageing and longevity. BACKGROUND: Leucocyte telomere length (LTL) is a complex trait associated with ageing and longevity. LTL dynamics are defined by LTL and its age-dependent attrition. Strong, but indirect evidence suggests that LTL at birth and its attrition during childhood largely explains interindividual LTL variation among adults. A number of studies have estimated the heritability of LTL, but none has assessed the heritability of age-dependent LTL attrition.METHODS: We examined the heritability of LTL dynamics based on a longitudinal evaluation (an average follow-up of 12 years) in 355 monozygotic and 297 dizygotic same-sex twins (aged 19-64 years at baseline).RESULTS: Heritability of LTL at baseline was estimated at 64% (95% CI 39% to 83%) with 22% (95% CI 6% to 49%) of shared environmental effects. Heritability of age-dependent LTL attrition rate was estimated at 28% (95% CI 16% to 44%). Individually unique environmental factors, estimated at 72% (95% CI 56% to 84%) affected LTL attrition rate with no indication of shared environmental effects.CONCLUSIONS: This is the first study that estimated heritability of LTL and also its age-dependent attrition. As LTL attrition is much slower in adults than in children and given that having a long or a short LTL is largely determined before adulthood, our findings suggest that heritability and early life environment are the main determinants of LTL throughout the human life course. Thus, insights into factors that influence LTL at birth and its dynamics during childhood are crucial for understanding the role of telomere genetics in human ageing and longevity.

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P

Kaprio, Jaakko/0000-0002-3716-2455; Knafo-Noam, Ariel/0000-0003-0613-1960; de Freitas, Duarte Luis/0000-0001-6642-3370; Haworth, Claire/0000-0002-8608-289X; Siribaddana, Sisira/0000-0001-5821-2557; Kyvik, Kirsten O/0000-0003-2981-0245; Aliev, Fazil/0000-0001-8357-4699; Craig, Jeffrey M/0000-0003-3979-7849; Ordonana, Juan R./0000-0001-7779-6017; Sund, Reijo/0000-0002-6268-8117; Bartels, Meike/0000-0002-9667-7555; Kandler, Christian/0000-0002-9175-235X; Fagnani, Corrado/0000-0001-5771-7772; Huibregtse, Brooke M./0000-0003-0977-7249; Montgomery, Grant W/0000-0002-4140-8139; Colodro-Conde, Lucia/0000-0002-9004-364X; Loos, Ruth J F/0000-0002-8532-5087; Busjahn, Andreas/0000-0001-9650-6919; ONCEL, Sevgi YURT/0000-0002-0990-292X; Christensen, Kaare/0000-0002-5429-5292; Martin, Nicholas/0000-0003-4069-8020; Tan, Qihua/0000-0003-3194-0030; ROMERA, JUAN FRANCISCO SANCHEZ/0000-0002-5405-6216; D'Ippolito, Cristina/0000-0001-7902-9380; Skytthe, Axel E/0000-0002-8629-4913; Tan, Qihua/0000-0003-3194-0030; Heikkila, Kauko/0000-0002-9256-8028; Duncan, Glen/0000-0001-6909-1869; Jelenkovic, Aline/0000-0002-6191-8371; Magnusson, Patrik/0000-0002-7315-7899; mangino, massimo/0000-0002-2167-7470; Medland, Sarah E/0000-0003-1382-380X; Saffery, Richard/0000-0002-9510-4181; Plomin, Robert/0000-0002-0756-3629; Harden, Kathryn/0000-0002-1557-6737; Hotopf, Matthew/0000-0002-3980-4466; McAdams, Tom/0000-0002-6825-3499; Aaltonen, Sari/0000-0002-2873-4263; Kremen, William/0000-0002-8629-5609; Pahlen, Shandell/0000-0003-0753-4155; Llewellyn, Clare/0000-0002-0066-2827; Franz, Carol/0000-0002-8987-1755; Derom, Catherine/0000-0001-5574-796X; Willemsen, Gonneke/0000-0003-3755-0236; Rasmussen, Finn/0000-0001-7915-7809; Rebato, Esther/0000-0003-1221-8501; lee, kayoung/0000-0002-2816-554X; Sodemann, Morten/0000-0001-8992-2500; Gatz, Margaret/0000-0002-1071-9970; Boivin, Michel/0000-0001-8621-9844; Silventoinen, Karri/0000-0003-1759-3079 WOS: 000358874400002 PubMed: 26014041 For over 100 years, the genetics of human anthropometric traits has attracted scientific interest. In particular, height and body mass index (BMI, calculated as kg/m(2)) have been under intensive genetic research. However, it is still largely unknown whether and how heritability estimates vary between human populations. Opportunities to address this question have increased recently because of the establishment of many new twin cohorts and the increasing accumulation of data in established twin cohorts. We started a new research project to analyze systematically (1) the variation of heritability estimates of height, BMI and their trajectories over the life course between birth cohorts, ethnicities and countries, and (2) to study the effects of birth-related factors, education and smoking on these anthropometric traits and whether these effects vary between twin cohorts. We identified 67 twin projects, including both monozygotic (MZ) and dizygotic (DZ) twins, using various sources. We asked for individual level data on height and weight including repeated measurements, birth related traits, background variables, education and smoking. By the end of 2014, 48 projects participated. Together, we have 893,458 height and weight measures (52% females) from 434,723 twin individuals, including 201,192 complete twin pairs (40% monozygotic, 40% same-sex dizygotic and 20% opposite-sex dizygotic) representing 22 countries. This project demonstrates that large-scale international twin studies are feasible and can promote the use of existing data for novel research purposes. National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [R01 MH58354]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [1RO1-AG13662-01A2]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R21 AG039572]; WT Grant Foundation; University of London Central Research fund; Medical Research CouncilMedical Research Council UK (MRC) [G81/343, G120/635]; Economic and Social Research CouncilEconomic & Social Research Council (ESRC) [RES-000-22-2206]; Institute of Social Psychiatry [06/07-11]; Leverhulme Research FellowshipLeverhulme Trust [RF/2/RFG/2008/0145]; Goldsmiths; University of London; National Research Foundation of KoreaNational Research Foundation of Korea [NRF-371-2011-1B00047]; Danish Agency for Science, Technology and Innovation; Research Council for Health and Disease; Velux Foundation; US National Institute of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P01 AG08761]; Fund of Scientific Research, FlandersFWO; Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium); Global Research Network Program of the National Research Foundation [NRF 2011-220-E00006]; NIDAUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Drug Abuse (NIDA) [DA011015]; Longitudinal Twin Study [HD10333]; National Institute of Health grantsUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [NIA R01 AG018384, R01 AG018386, R01 AG022381, R01 AG022982]; Cooperative Studies Program of the Office of Research AMP; Development of the United States Department of Veterans Affairs; Centre of Research Excellence from the National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1079102]; Michigan State University from the National Institute of Mental Health (NIMH) [R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01]; Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD) [R01-HD066040]; MSU Foundation [11-SPG-2518]; California Tobacco-Related Disease Research ProgramUniversity of California System [7RT-0134H, 8RT-0107H, 6RT-0354H]; The National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [1R01ESO15150-01]; National Natural Science Foundation of ChinaNational Natural Science Foundation of China [81125007]; Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [437015, 607358]; Bonnie Babes Foundation [BBF20704]; Financial Markets Foundation for Children [032-2007]; Victorian Government's Operational Infrastructure Support Program; ENGAGE-European Network for Genetic and Genomic Epidemiology [201413]; National Institute of Alcohol Abuse and AlcoholismUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Alcohol Abuse & Alcoholism (NIAAA) [AA-12502, AA-00145, AA-09203]; Academy of Finland Center of Excellence in Complex Disease GeneticsAcademy of Finland [213506, 129680]; Academy of FinlandAcademy of Finland [100499, 205585, 118555, 141054, 265240, 263278, 264146]; Osaka University's International Joint Research Promotion Program; Kirikkale University Research Grant: KKUKirikkale University; TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [114C117]; European Research Council (ERC)European Research Council (ERC) [240994]; European Union's Seventh Framework Programmes ENGAGE ConsortiumEuropean Union (EU) [HEALTH-F4-2007-201413]; BioSHaRE EU [HEALTH-F4-2010-261433]; Seneca FoundationFundacion Seneca; Regional Agency for Science and Technology, Murcia, Spain [08633/PHCS/08, 15302/PHCS/10]; Ministry of Science and Innovation, SpainSpanish Government [PSI11560-2009]; UK Medical Research CouncilMedical Research Council UK (MRC) [G0901245]; UK Biotechnology and Biological Sciences Research CouncilBiotechnology and Biological Sciences Research Council (BBSRC) [31/D19086]; Portuguese agency for research (The Foundation for Science and Technology) [POCI/DES/56834/2004]; National Institutes of Health.United States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HD068435, R01 MH062375]; Wellcome TrustWellcome Trust; European Community's Seventh Framework ProgrammeEuropean Union (EU); National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London; Netherlands Organization for Scientific Research (NWO)Netherlands Organization for Scientific Research (NWO); MagW/ZonMW [904-61-090, 985-10-002, 912-10-020, 904-61-193, 480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192]; VU University's Institute for Health and Care Research (EMGO+); European Research CouncilEuropean Research Council (ERC) [ERC-230374]; Avera Institute, Sioux Falls, South Dakota (USA); Cancer Research UKCancer Research UK [C1418/A7974]; [5T32DA017637-10]; [NIH RC2 HL103416]; Cancer Research UKCancer Research UK [14133]; Medical Research CouncilMedical Research Council UK (MRC) [G0901245, MC_UU_12013/1]; NNF Center for Basic Metabolic ResearchNovo Nordisk Foundation [Metabolic Genetics]; Novo Nordisk FondenNovo NordiskNovo Nordisk Foundation [NNF10CC1016515] This study was conducted within the CODATwins project (Academy of Finland #266592). Support for participating twin projects: the University of Southern California Twin Study is funded by a grant from the National Institute of Mental Health (R01 MH58354). The Carolina African American Twin Study of Aging (CAATSA) was funded by a grant from the National Institute on Aging (grant 1RO1-AG13662-01A2) to K. E. Whitfield. The NAS-NRC Twin Registry acknowledges financial support from the National Institutes of Health grant number R21 AG039572. Waves 1-3 of Genesis 12-19 were funded by the WT Grant Foundation, the University of London Central Research fund and a Medical Research Council Training Fellowship (G81/343) and Career Development Award (G120/635) to Thalia C. Eley. Wave 4 was supported by grants from the Economic and Social Research Council (RES-000-22-2206) and the Institute of Social Psychiatry (06/07-11) to Alice M. Gregory who was also supported at that time by a Leverhulme Research Fellowship (RF/2/RFG/2008/0145). Wave 5 was supported by funding to Alice M. Gregory from Goldsmiths, University of London. Anthropometric measurements of the Hungarian twins were supported by Medexpert Ltd., Budapest, Hungary. South Korea Twin Registry is supported by National Research Foundation of Korea (NRF-371-2011-1B00047). The Danish Twin Registry is supported by the National Program for Research Infrastructure 2007 from the Danish Agency for Science, Technology and Innovation, The Research Council for Health and Disease, the Velux Foundation and the US National Institute of Health (P01 AG08761). Since its origin, the East Flanders Prospective Survey has been partly supported by grants from the Fund of Scientific Research, Flanders and Twins, a non-profit Association for Scientific Research in Multiple Births (Belgium). Korean Twin-Family Register was supported by the Global Research Network Program of the National Research Foundation (NRF 2011-220-E00006). The Colorado Twin Registry is funded by NIDA funded center grant DA011015 and Longitudinal Twin Study HD10333; Author Huibregtse is supported by 5T32DA017637-10. The Vietnam Era Twin Study of Aging was supported by National Institute of Health grants NIA R01 AG018384, R01 AG018386, R01 AG022381, and R01 AG022982, and, in part, with resources of the VA San Diego Center of Excellence for Stress and Mental Health. The Cooperative Studies Program of the Office of Research & Development of the United States Department of Veterans Affairs has provided financial support for the development and maintenance of the Vietnam Era Twin (VET) Registry. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIA/NIH, or the VA. The Australian Twin Registry is supported by a Centre of Research Excellence (grant ID 1079102) from the National Health and Medical Research Council administered by the University of Melbourne. The Michigan State University Twin Registry has been supported by Michigan State University, as well as grants R01-MH081813, R01-MH0820-54, R01-MH092377-02, R21-MH070542-01, R03-MH63851-01 from the National Institute of Mental Health (NIMH), R01-HD066040 from the Eunice Kennedy Shriver National Institute for Child Health and Human Development (NICHD), and 11-SPG-2518 from the MSU Foundation. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the NIMH, the NICHD, or the National Institutes of Health.; r The California Twin Program was supported by The California Tobacco-Related Disease Research Program (7RT-0134H, 8RT-0107H, 6RT-0354H) and the National Institutes of Health (1R01ESO15150-01). The Guangzhou Twin Eye Study is supported by National Natural Science Foundation of China (grant #81125007). PETS was supported by grants from the Australian National Health and Medical Research Council (grant numbers 437015 and 607358 to JC, and RS), the Bonnie Babes Foundation (grant number BBF20704 to JMC), the Financial Markets Foundation for Children (grant no. 032-2007 to JMC), and by the Victorian Government's Operational Infrastructure Support Program. Data collection and analyses in Finnish twin cohorts have been supported by ENGAGE-European Network for Genetic and Genomic Epidemiology, FP7-HEALTH-F4-2007, grant agreement number 201413, National Institute of Alcohol Abuse and Alcoholism (grants AA-12502, AA-00145, and AA-09203 to R. J. Rose, the Academy of Finland Center of Excellence in Complex Disease Genetics (grant numbers: 213506, 129680), and the Academy of Finland (grants 100499, 205585, 118555, 141054, 265240, 263278 and 264146 to J. Kaprio). K. Silventoinen is supported by Osaka University's International Joint Research Promotion Program. S. Y. Oncel and F. Aliev are supported by Kirikkale University Research Grant: KKU, 2009/43 and TUBITAK grant 114C117. The Longitudinal Israeli Study of Twins was funded by the Starting Grant no. 240994 from the European Research Council (ERC) to Ariel Knafo. Data collection and research stemming from the Norwegian Twin Registry is supported, in part, from the European Union's Seventh Framework Programmes ENGAGE Consortium (grant agreement HEALTH-F4-2007-201413, and BioSHaRE EU (grant agreement HEALTH-F4-2010-261433). The Murcia Twin Registry is supported by the Seneca Foundation, Regional Agency for Science and Technology, Murcia, Spain (08633/PHCS/08 & 15302/PHCS/10) and Ministry of Science and Innovation, Spain (PSI11560-2009). The Twins Early Development Study (TEDS) is supported by a program grant (G0901245) from the UK Medical Research Council and the work on obesity in TEDS is supported in part by a grant from the UK Biotechnology and Biological Sciences Research Council (31/D19086). The Madeira data comes from the following project: genetic and environmental influences on physical activity, fitness, and health: the Madeira family study Project reference: POCI/DES/56834/2004 founded by the Portuguese agency for research (The Foundation for Science and Technology). The Boston University Twin Project is funded by grants (#R01 HD068435 #R01 MH062375) from the National Institutes of Health to K. Saudino. TwinsUK was funded by the Wellcome Trust; European Community's Seventh Framework Programme (FP7/2007-2013). The study also receives support from the National Institute for Health Research (NIHR) BioResource Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust and King's College London. The University of Washington Twin Registry is supported by the grant NIH RC2 HL103416 (D. Buchwald, PI). The Netherlands Twin Register acknowledges the Netherlands Organization for Scientific Research (NWO) and MagW/ZonMW grants 904-61-090, 985-10-002, 912-10-020, 904-61-193,480-04-004, 463-06-001, 451-04-034, 400-05-717, Addiction-31160008, Middelgroot-911-09-032, Spinozapremie 56-464-14192; VU University's Institute for Health and Care Research (EMGO+); the European Research Council (ERC-230374), the Avera Institute, Sioux Falls, South Dakota (USA).; r Gemini was supported by a grant from Cancer Research UK (C1418/A7974).

Purpose: To determine the genetic contribution to the pattern of retinal vascular branching expressed by its fractal dimension.Methods: This was a cross-sectional study of 50-degree, disc-centred fundus photographs from 59 monozygotic and 55 dizygotic, same-sex twin pairs aged 20-46 years. The retinal vascular fractal dimension was measured using the box-counting method and compared within monozygotic and dizygotic twin pairs using Pearson correlation coefficents. Falconer´s formula and quantitative genetic models were used to determine the genetic component of variation.Results: The retinal vascular fractal dimensions were measurable for both twins in 50 monozygotic and 49 dizygotic twin pairs. The mean fractal dimension did not differ statistically significantly between monozygotic and dizygotic twin pairs (1.505 vs. 1.495, p=0.06), supporting that the study population was suitable for quantitative analysis of heritability. The intrapair correlation was markedly higher (0.505, p=0.0002) in monozygotic twins than in dizygotic twins (0.108, p=0.46), corresponding to a heritability h2 for the fractal dimension of 0.79. In quantitative genetic models, 54% of the variation was explained by dominant genetic effects and 46% was individually environmentally determined.Conclusion: In young adult twins, the branching pattern of the retinal vessels demonstrated a higher structural similarity in monozygotic than in dizygotic twin pairs. The retinal vascular fractal dimension was mainly determined by genetic factors, which accounted for 54% of the variation. The genetically predetermination of the

Ancestry information at the individual level can be a valuable resource for personalized medicine, medical, demographical and history research, as well as for tracing back personal history. We report a new method for quantitatively determining personal genetic ancestry based on genome-wide data. Numerical ancestry component scores are assigned to individuals based on comparisons with reference populations. These comparisons are conducted with an existing analytical pipeline making use of genotype phasing, similarity matrix computation and our addition-multidimensional best fitting by MixFit. The method is demonstrated by studying Estonian and Finnish populations in geographical context. We show the main differences in the genetic composition of these otherwise close European populations and how they have influenced each other. The components of our analytical pipeline are freely available computer programs and scripts one of which was developed in house (available at: www.geenivaramu.ee/en/tools/mixfit).

International audience; An ongoing debate in demography has focused on whether the human lifespan has a maximal natural limit. Taking a mechanistic perspective, and knowing that short telomeres are associated with diminished longevity, we examined whether telomere length dynamics during adult life could set a maximal natural lifespan limit. We define leukocyte telomere length of 5 kb as the 'telomeric brink', which denotes a high risk of imminent death. We show that a subset of adults may reach the telomeric brink within the current life expectancy and more so for a 100-year life expectancy. Thus, secular trends in life expectancy should confront a biological limit due to crossing the telomeric brink.

BACKGROUND: Smoking is a major risk factor for lung diseases and lower respiratory symptoms, but since not all smokers develop chronic bronchitis and since chronic bronchitis is also diagnosed in never-smokers, it has been suggested that some individuals are more susceptible to develop chronic bronchitis due to genetics.OBJECTIVE: To study the relative influence of genetic and environmental factors on the variation in the susceptibility to chronic bronchitis.METHODS: In a population-based questionnaire study of 13,649 twins, 50-71 years of age, from the Danish Twin Registry, we calculated sex-specific concordance rates and heritability of chronic bronchitis. The response rate was 75%.RESULTS: The prevalence of chronic bronchitis was 9.3% among men and 8.5% among women. The concordance rate for chronic bronchitis was higher in monozygotic twins than in dizygotic twins among women; 0.30 vs. 0.17, but not among men; 0.15 vs. 0.18. The heritability of chronic bronchitis adjusted for smoking and age was 55% (36-71%) in women, whereas the susceptibility to chronic bronchitis in men for 25% (8-41%) was ascribable to familial environment but not to genetic factors.CONCLUSIONS: Chronic bronchitis shows a moderate familial aggregation, particularly in women. Increased susceptibility to respiratory disease among female smokers relative to male smokers may have a genetic origin. BACKGROUND: Smoking is a major risk factor for lung diseases and lower respiratory symptoms, but since not all smokers develop chronic bronchitis and since chronic bronchitis is also diagnosed in never-smokers, it has been suggested that some individuals are more susceptible to develop chronic bronchitis due to genetics.OBJECTIVE: To study the relative influence of genetic and environmental factors on the variation in the susceptibility to chronic bronchitis.METHODS: In a population-based questionnaire study of 13,649 twins, 50-71 years of age, from the Danish Twin Registry, we calculated sex-specific concordance rates and heritability of chronic bronchitis. The response rate was 75%.RESULTS: The prevalence of chronic bronchitis was 9.3% among men and 8.5% among women. The concordance rate for chronic bronchitis was higher in monozygotic twins than in dizygotic twins among women; 0.30 vs. 0.17, but not among men; 0.15 vs. 0.18. The heritability of chronic bronchitis adjusted for smoking and age was 55% (36-71%) in women, whereas the susceptibility to chronic bronchitis in men for 25% (8-41%) was ascribable to familial environment but not to genetic factors.CONCLUSIONS: Chronic bronchitis shows a moderate familial aggregation, particularly in women. Increased susceptibility to respiratory disease among female smokers relative to male smokers may have a genetic origin.