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Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis

Zöller, Bengt LU orcid ; Pirouzifard, Mirnabi LU ; Svensson, Peter J. LU ; Holmquist, Björn LU orcid ; Stenman, Emelie LU ; Elston, Robert C. ; Song, Yuenjoo E. ; Sundquist, Jan LU and Sundquist, Kristina LU (2021) In Journal of the American Heart Association 10(24).
Abstract
Background
This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance.

Methods and Results
The Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE.... (More)
Background
This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance.

Methods and Results
The Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred.

Conclusions
This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance. (Less)
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author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
epidemiology, genetics, heritability, segregation analysis, venous thromboembolism
in
Journal of the American Heart Association
volume
10
issue
24
article number
e020323
publisher
Wiley-Blackwell
external identifiers
  • pmid:34913365
  • scopus:85122904187
ISSN
2047-9980
DOI
10.1161/JAHA.120.020323
language
English
LU publication?
yes
id
22ed84c7-d2e4-42b0-9a2d-24b4c004287d
date added to LUP
2022-02-02 17:28:43
date last changed
2022-08-02 08:12:16
@article{22ed84c7-d2e4-42b0-9a2d-24b4c004287d,
  abstract     = {{Background<br/>This is the first nationwide segregation analysis that aimed to determine whether familial venous thromboembolism (VTE) is attributable to inheritance and/or shared environment, and the possible mode of inheritance.<br/><br/>Methods and Results<br/>The Swedish Multi‐Generation Register was linked to the Swedish patient register for the period 1964 to 2015. Three generational families of Swedish‐born individuals were identified. Heritability was examined using Falconer regression. Complex segregation analysis was conducted using the Statistical Analysis for Genetic Epidemiology software (version 6.4, 64‐bit Linux). Among the 4 301 174 relatives from 450 558 pedigrees, 177 865 (52% women) individuals were affected with VTE. VTE occurred in 2 or more affected relatives in 61 217 (13.6%) of the pedigrees. Heritability showed age and sex dependence with higher heritability for men and young individuals. In 18 933 pedigrees, VTE occurred only in the first generation and was not inherited. Segregation analysis was performed in the remaining 42 284 pedigrees with inherited VTE and included 939 192 individuals. Prevalence constraints were imposed in the models to allow for the selection of the pedigrees analyzed. The sporadic nongenetic model could be discarded. The major‐type‐only model, with a correlation structure compatible with some polygenic effects, was the preferred model. Among the Mendelian models, the mixed codominant (plus polygenic) model was preferred.<br/><br/>Conclusions<br/>This nationwide segregation analysis of VTE supports a genetic cause of the familial aggregation of VTE. Heritability was higher for men and younger individuals, suggesting a Carter effect, in agreement with a multifactorial threshold inheritance.}},
  author       = {{Zöller, Bengt and Pirouzifard, Mirnabi and Svensson, Peter J. and Holmquist, Björn and Stenman, Emelie and Elston, Robert C. and Song, Yuenjoo E. and Sundquist, Jan and Sundquist, Kristina}},
  issn         = {{2047-9980}},
  keywords     = {{epidemiology; genetics; heritability; segregation analysis; venous thromboembolism}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{24}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Journal of the American Heart Association}},
  title        = {{Familial Segregation of Venous Thromboembolism in Sweden: A Nationwide Family Study of Heritability and Complex Segregation Analysis}},
  url          = {{http://dx.doi.org/10.1161/JAHA.120.020323}},
  doi          = {{10.1161/JAHA.120.020323}},
  volume       = {{10}},
  year         = {{2021}},
}