Full Length Article A sibling based design to quantify genetic and shared environmental effects of venous thromboembolism in Sweden Bengt Zöller, MD, PhD ⁎, Henrik Ohlsson, PhD, Jan Sundquist, MD, PhD, Kristina Sundquist, MD, PhD Center for Primary Health Care Research, Lund University, Malmö, Sweden abstract article info Article history: Received 30 May 2016 Received in revised form 9 October 2016 Accepted 14 October 2016 Available online 20 October 2016 Introduction: Few large studies have examined the heritability of venous thromboembolism (VTE). Moreover, twin studies have been suggested to overestimate heritability. The aim of the present study was to determine the heritability nationwide in the general Swedish population using full siblings and half-siblings. Methods: VTE was defined using the Swedish patient register. Full sibling (FS) and half-sibling (HS) pairs born 1950–1990 were obtained from the Swedish Multi-generation Register. A maximum of 5 years age difference was allowed. We also required that the individuals within the pair should reside in the same household for at least 8 years or not at all (0 years) before the youngest turned 16. Information about sibling pair residence within the same household, small residential area, and municipality was obtained from Statistics Sweden. We assumed three potential sources of liability to VTE: additive genetic (A), shared (or common/familial) environment (C), and unique environment (E) components. Results: Totally 881,206 FS pairs and 95,198 HS pairs were included. The full model predicted heritability for VTE with 47% for males and 40% for females. Environmental factors shared by siblings contributed to 0% of the vari- ance in liability for both sexes, and unique environment (E) components accounted for 53% in males and 60% in females. Conclusion: The high heritability of VTE risk indicates that genetic susceptibility plays a substantial role for VTE in the Swedish general population. Overestimation of heritability from twin studies is not likely. The proportion of the variance attributable to shared familial environment factors is small. Subject codes: Genetics, epidemiology, thrombosis, cardiovascular disease, embolism © 2016 Elsevier Ltd. All rights reserved. Keywords: Genetics Genetic predisposition to disease Venous thromboembolism Venous thrombosis Epidemiological studies 1. Introduction Venous thromboembolism [VTE] is a serious medical diagnosis which affects approximately 1–2 per 1000 individuals per year [1–3] and often runs in families. Familial thrombophilia, e.g. clustering of VTE, was recognized at the beginning of the 20th century [4]. Like many common human diseases and traits that cluster in families, VTE is considered to be a complex disorder influenced by several genetic and environmental factors [5,6]. Inherited deficiencies of the natural an- ticoagulant inhibitors antithrombin, protein C and proteins S, as well as activated protein C resistance (APC resistance) due to the FV Leiden mu- tation (rs6025) and the prothrombin 20210A mutation (rs1799963), have been associated with familial thrombophilia [5,6]. The five major identified genetic risk factors for VTE together account for only about 30% of the family history [7]. Newly identified common, but much weaker, alleles probably only contribute to a fraction of the familial risk for VTE [8,9]. Thus, as for many other complex disorders, the source of the missing heritability of VTE remains to be determined. 10 The miss- ing heritability of VTE might be genetic, epigenetic or non-genetic (due to familial environmental effects) [10]. Shared familial environmental factors might be related to socioeconomic factors such as poverty and low educational level but also health behaviours such as high alcohol consumption, drug abuse, smoking, physical inactivity, and unhealthy food habits [11]. Heritability of VTE, that is, the proportion of the variance attributable to genetic effects on VTE, has been estimated to be 50–60% in one twin study and two extended family studies [12–14]. However, the twin study was very small and non-significant for women [12]. There were only 11 concordant male monozygotic pairs and 8 dizygotic male pairs, one concordant female monozygotic pair and no dizygotic female pairs. However, the validity of the twin method has been questioned, with critics suggesting that the resulting heritability estimates might be inflated [15]. Twins also have a distinct shared intra-uterine experi- ence and form, it is claimed, a unique psychological relationship so that results derived from them cannot be extrapolated to more typical human populations [15]. Thrombosis Research 149 (2017) 82–87 ⁎ Corresponding author at: Center for Primary Health Care Research, Clinical Research Center, Floor 11, Building 28, Entrance 72, Malmö University Hospital, S-205 02 Malmö, Sweden. E-mail address: bengt.zoller@med.lu.se (B. Zöller). http://dx.doi.org/10.1016/j.thromres.2016.10.014 0049-3848/© 2016 Elsevier Ltd. All rights reserved. Contents lists available at ScienceDirect Thrombosis Research journal homepage: www.elsevier.com/locate/thromres