title: Familiality and SNP heritability of age at onset and episodicity in major depressive disorder.
abstract: BACKGROUND
  Strategies to dissect phenotypic and genetic heterogeneity of major depressive disorder (MDD) have mainly relied on subphenotypes, such as age at onset (AAO) and recurrence/episodicity. Yet, evidence on whether these subphenotypes are familial or heritable is scarce. The aims of this study are to investigate the familiality of AAO and episode frequency in MDD and to assess the proportion of their variance explained by common single nucleotide polymorphisms (SNP heritability).
  
  
  METHODS
  For investigating familiality, we used 691 families with 2-5 full siblings with recurrent MDD from the DeNt study. We fitted (square root) AAO and episode count in a linear and a negative binomial mixed model, respectively, with family as random effect and adjusting for sex, age and center. The strength of familiality was assessed with intraclass correlation coefficients (ICC). For estimating SNP heritabilities, we used 3468 unrelated MDD cases from the RADIANT and GSK Munich studies. After similarly adjusting for covariates, derived residuals were used with the GREML method in GCTA (genome-wide complex trait analysis) software.
  
  
  RESULTS
  Significant familial clustering was found for both AAO (ICC = 0.28) and episodicity (ICC = 0.07). We calculated from respective ICC estimates the maximal additive heritability of AAO (0.56) and episodicity (0.15). SNP heritability of AAO was 0.17 (p = 0.04); analysis was underpowered for calculating SNP heritability of episodicity.
  
  
  CONCLUSIONS
  AAO and episodicity aggregate in families to a moderate and small degree, respectively. AAO is under stronger additive genetic control than episodicity. Larger samples are needed to calculate the SNP heritability of episodicity. The described statistical framework could be useful in future analyses.
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: P
authors.initials: P
authors.lastname: Ferentinos
authors.affiliation: Department of Biostatistics,Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: A
authors.initials: A
authors.lastname: Koukounari
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: R
authors.initials: R
authors.lastname: Power
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: M
authors.initials: M
authors.lastname: Rivera
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: R
authors.initials: R
authors.lastname: Uher
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics,Neuroscience and Mental Health Research Institute, Cardiff University,Cardiff,UK.
authors.forename: N
authors.initials: N
authors.lastname: Craddock
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics,Neuroscience and Mental Health Research Institute, Cardiff University,Cardiff,UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Barts and The London Medical School, Queen Mary University of London,London,UK.
authors.forename: A
authors.initials: A
authors.lastname: Korszun
authors.affiliation: Department of Psychiatry,University of Birmingham,Birmingham,UK.
authors.forename: L
authors.initials: L
authors.lastname: Jones
authors.affiliation: MRC Centre for Neuropsychiatric Genetics and Genomics,Neuroscience and Mental Health Research Institute, Cardiff University,Cardiff,UK.
authors.forename: I
authors.initials: I
authors.lastname: Jones
authors.affiliation: Department of Psychiatry,Trinity Centre for Health Science,Dublin,Ireland.
authors.forename: M
authors.initials: M
authors.lastname: Gill
authors.affiliation: Department of Psychiatry,Washington University,St. Louis, Missouri,USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Rice
authors.affiliation: Max Planck Institute of Psychiatry,Munich,Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ising
authors.affiliation: Department of Psychiatry,University of Bonn & German Center of Neurodegenerative Diseases (DZNE),Bonn,Germany.
authors.forename: W
authors.initials: W
authors.lastname: Maier
authors.affiliation: Centre for Psychiatric Research,Aarhus University Hospital,Risskov,Denmark.
authors.forename: O
authors.initials: O
authors.lastname: Mors
authors.affiliation: Division of Genetic Epidemiology in Psychiatry,Central Institute of Mental Health,Mannheim,Germany.
authors.forename: M
authors.initials: M
authors.lastname: Rietschel
authors.affiliation: University Hospital Center and University of Lausanne,Lausanne,Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Preisig
authors.affiliation: Max Planck Institute of Psychiatry,Munich,Germany.
authors.forename: E B
authors.initials: EB
authors.lastname: Binder
authors.affiliation: Departments of Psychiatry and Medical Genetics,University of Alberta,Edmonton, Alberta,Canada.
authors.forename: K J
authors.initials: KJ
authors.lastname: Aitchison
authors.affiliation: Department of Psychiatry,Free University of Brussels,Brussels,Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Mendlewicz
authors.affiliation: Centre Européen de Psychologie Médicale PSY-PLURIEL,Bruxelles,Belgium.
authors.forename: D
authors.initials: D
authors.lastname: Souery
authors.affiliation: Department of Genetics in Psychiatry,Poznan University of Medical Sciences,Poznan,Poland.
authors.forename: J
authors.initials: J
authors.lastname: Hauser
authors.affiliation: Department of Psychiatry,University of Zagreb,Zagreb,Croatia.
authors.forename: N
authors.initials: N
authors.lastname: Henigsberg
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: G
authors.initials: G
authors.lastname: Breen
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: I W
authors.initials: IW
authors.lastname: Craig
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: A E
authors.initials: AE
authors.lastname: Farmer
authors.affiliation: Max Planck Institute of Psychiatry,Munich,Germany.
authors.forename: B
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: P
authors.initials: P
authors.lastname: McGuffin
authors.affiliation: MRC Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, Psychology and Neuroscience, King's College London,London,UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Lewis
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D003865:Major Depressive Disorder / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005858:Germany; D006801:Humans; D007407:Interviews as Topic; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011110:Polymorphism, Genetic; D035781:Siblings; D006113:United Kingdom; D055815:Young Adult
keywords: Age at onset; GCTA; episodicity; familiality; heritability; major depression