title: Estimating Heritability of Prostate Cancer-Specific Survival Using Population-Based Registers.
abstract: BACKGROUND
  There is a strong genetic component in prostate cancer development with an estimated heritability of 58%. In addition, recent epidemiological assessments show a familial component in prostate cancer-specific survival, which could be due to either common genetics or environment. In this study we sought to estimate the heritability of prostate cancer-specific survival by studying brothers and father-son pairs in Sweden.
  
  
  METHODS
  We used linkage records from three Swedish national registers: the Multi-Generation Register, the Cancer Register, and the Cause of Death Register. One thousand seven hundred twenty-eight brother pairs and 6,444 father-son pairs, where both family members were diagnosed with prostate cancer, were followed for prostate cancer mortality. By assuming that (i) brothers on average share 50% of their segregating alleles and 100% environment and (ii) fathers and sons share 50% of their segregating alleles and no environment, we implemented a model including influences of additive genetics (heritability), shared environment and non-shared environment for survival data. A conditional likelihood estimation procedure was developed to fit the model. Data simulation was applied to validate model assumptions.
  
  
  RESULTS
  In a model that adjusted for age at diagnosis and calendar period, the estimated heritability of prostate cancer-specific survival was 0.10 (95% CI = 0.00-0.20) that was borderline significantly different from zero (P = 0.057). The shared environment component was not significantly different from zero with a point estimate of 0.00 (95% CI = 0.00-0.13). Simulation studies and sensitivity analysis revealed that the estimated heritability component was robust, whereas the shared environmental component may be underestimated.
  
  
  CONCLUSIONS
  Heritability of prostate cancer-specific survival is considerably lower than for prostate cancer incidence. This supports a hypothesis that susceptibility of disease and progression of disease are separate mechanisms that involve different genes. Further assessment of the genetic basis of prostate cancer-specific survival is warranted. Prostate 77:900-907, 2017. © 2017 Wiley Periodicals, Inc.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.|Division of Family Medicine, Department of Neurobiology, Care Science and Society, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Robert
authors.identifier: http://orcid.org/0000-0003-3423-4668
authors.initials: R
authors.lastname: Szulkin
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Clements
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Patrik K E
authors.initials: PKE
authors.lastname: Magnusson
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fredrik E
authors.initials: FE
authors.lastname: Wiklund
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kuja-Halkola
mesh_terms: D000328:Adult; D000368:Aged; D018450:Disease Progression; D004198:Disease Susceptibility / Q000453:epidemiology*; D005190:Family; D059647:Gene-Environment Interaction; D006801:Humans; D015994:Incidence; D040582:Inheritance Patterns; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics / Q000401:mortality; D012042:Registries; D016019:Survival Analysis; D013548:Sweden / Q000453:epidemiology
keywords: ACE-model; heritability; population-based registers; prostate cancer-specific survival