title: Familial segregation of venous thromboembolism.
abstract: BACKGROUND
  Venous thromboembolism (VTE) is postulated as a complex disease, but the heritability and mode of inheritance are uncertain.
  
  
  OBJECTIVE
  To determine if VTE (i) segregates in families; (ii) is attributable to inheritance, shared environment, or both; and (iii) the possible mode of inheritance.
  
  
  METHODS
  In a family-based study of relatives from 751 probands (60% female) with objectively diagnosed VTE (without cancer), we performed complex segregation analyses corrected for mode of ascertainment, considering age-specific, non-gender- and gender-specific liability classes under Mendelian and non-Mendelian assumptions. We tested 12 models categorized into four model sets: (i) sporadic (assumes no genetic effect); (ii) Mendelian inheritance of a major gene (including dominant, additive, recessive or codominant classes); (iii) mixed model (Mendelian inheritance including the same four classes plus the effect of polygenes); and (iv) non-Mendelian.
  
  
  RESULTS
  Among the 16 650 relatives, 753 (48% female) were affected with VTE, of whom 62% were first-degree relatives. The sporadic model was rejected in both non-gender- and gender-specific liability class analyses. Among the remaining gender-specific models, the unrestricted (non-Mendelian) inheritance model was favored with an estimated heritability of 0.52. Among the Mendelian models, the dominant mixed model was preferred, with an estimated heritability and major disease allele frequency of 0.62 and 0.25, respectively, suggesting an effect of several minor genes.
  
  
  CONCLUSIONS
  A multifactorial non-Mendelian inheritance model was favored as the cause for VTE, while a model postulating a purely environmental cause was rejected. VTE is probably a result of multigenic action as well as environmental exposures.
authors.affiliation: Division of Cardiovascular Diseases, Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA. heit.john@mayo.edu
authors.forename: J A
authors.initials: JA
authors.lastname: Heit
authors.forename: M A
authors.initials: MA
authors.lastname: Phelps
authors.forename: S A
authors.initials: SA
authors.lastname: Ward
authors.forename: J P
authors.initials: JP
authors.lastname: Slusser
authors.forename: T M
authors.initials: TM
authors.lastname: Petterson
authors.forename: M
authors.initials: M
authors.lastname: De Andrade
mesh_terms: D000293:Adolescent; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D040582:Inheritance Patterns; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D010375:Pedigree; D012737:Sex Factors; D013923:Thromboembolism / Q000209:etiology / Q000235:genetics*; D020246:Venous Thrombosis / Q000209:etiology / Q000235:genetics*