title: Epidemiology and Heritability of Major Depressive Disorder, Stratified by Age of Onset, Sex, and Illness Course in Generation Scotland: Scottish Family Health Study (GS:SFHS).
abstract: The heritability of Major Depressive Disorder (MDD) has been estimated at 37% based largely on twin studies that rely on contested assumptions. More recently, the heritability of MDD has been estimated on large populations from registries such as the Swedish, Finnish, and Chinese cohorts. Family-based designs utilise a number of different relationships and provide an alternative means of estimating heritability. Generation Scotland: Scottish Family Health Study (GS:SFHS) is a large (n = 20,198), family-based population study designed to identify the genetic determinants of common diseases, including Major Depressive Disorder. Two thousand seven hundred and six individuals were SCID diagnosed with MDD, 13.5% of the cohort, from which we inferred a population prevalence of 12.2% (95% credible interval: 11.4% to 13.1%). Increased risk of MDD was associated with being female, unemployed due to a disability, current smokers, former drinkers, and living in areas of greater social deprivation. The heritability of MDD in GS:SFHS was between 28% and 44%, estimated from a pedigree model. The genetic correlation of MDD between sexes, age of onset, and illness course were examined and showed strong genetic correlations. The genetic correlation between males and females with MDD was 0.75 (0.43 to 0.99); between earlier (≤ age 40) and later (> age 40) onset was 0.85 (0.66 to 0.98); and between single and recurrent episodic illness course was 0.87 (0.72 to 0.98). We found that the heritability of recurrent MDD illness course was significantly greater than the heritability of single MDD illness course. The study confirms a moderate genetic contribution to depression, with a small contribution of the common family environment (variance proportion = 0.07, CI: 0.01 to 0.15), and supports the relationship of MDD with previously identified risk factors. This study did not find robust support for genetic differences in MDD due to sex, age of onset, or illness course. However, we found an intriguing difference in heritability between recurrent and single MDD illness course. These findings establish GS:SFHS as a valuable cohort for the genetic investigation of MDD.
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Fernandez-Pujals
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Mark James
authors.initials: MJ
authors.lastname: Adams
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Pippa
authors.initials: P
authors.lastname: Thomson
authors.affiliation: The Patrick Wild Centre, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: McKechanie
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Douglas H R
authors.initials: DH
authors.lastname: Blackwood
authors.affiliation: Division of Population Health Science, University of Dundee, Dundee, United Kingdom.
authors.forename: Blair H
authors.initials: BH
authors.lastname: Smith
authors.affiliation: College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Anna F
authors.initials: AF
authors.lastname: Dominiczak
authors.affiliation: Usher Institute of Population Health Sciences and Informatics University of Edinburgh, Bioquarter, Edinburgh, United Kingdom.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.affiliation: Division of Neuroscience, University of Dundee, Dundee, United Kingdom.
authors.forename: Keith
authors.initials: K
authors.lastname: Matthews
authors.affiliation: Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Archie
authors.initials: A
authors.lastname: Campbell
authors.affiliation: Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Pamela
authors.initials: P
authors.lastname: Linksted
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Chris S
authors.initials: CS
authors.lastname: Haley
authors.affiliation: Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Deary
authors.affiliation: Generation Scotland, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Porteous
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: MacIntyre
authors.affiliation: Division of Psychiatry, University of Edinburgh, Edinburgh, United Kingdom.|Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: McIntosh
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D015331:Cohort Studies; D003865:Major Depressive Disorder / Q000453:epidemiology* / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D015995:Prevalence; D012042:Registries; D012307:Risk Factors; D012606:Scotland / Q000453:epidemiology; D012737:Sex Factors; D011795:Surveys and Questionnaires; D055815:Young Adult