title: Missing heritability: is the gap closing? An analysis of 32 complex traits in the Lifelines Cohort Study.
abstract: Despite the recent explosive rise in number of genetic markers for complex disease traits identified in genome-wide association studies, there is still a large gap between the known heritability of these traits and the part explained by these markers. To gauge whether this 'heritability gap' is closing, we first identified genome-wide significant SNPs from the literature and performed replication analyses for 32 highly relevant traits from five broad disease areas in 13 436 subjects of the Lifelines Cohort. Next, we calculated the variance explained by multi-SNP genetic risk scores (GRSs) for each trait, and compared it to their broad- and narrow-sense heritabilities captured by all common SNPs. The majority of all previously-associated SNPs (median=75%) were significantly associated with their respective traits. All GRSs were significant, with unweighted GRSs generally explaining less phenotypic variance than weighted GRSs, for which the explained variance was highest for height (15.5%) and varied between 0.02 and 6.7% for the other traits. Broad-sense common-SNP heritability estimates were significant for all traits, with the additive effect of common SNPs explaining 48.9% of the variance for height and between 5.6 and 39.2% for the other traits. Dominance effects were uniformly small (0-1.5%) and not significant. On average, the variance explained by the weighted GRSs accounted for only 10.7% of the common-SNP heritability of the 32 traits. These results indicate that GRSs may not yet be ready for accurate personalized prediction of complex disease traits limiting widespread adoption in clinical practice.
authors.affiliation: Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ilja M
authors.identifier: 0000-0001-5047-4077
authors.initials: IM
authors.lastname: Nolte
authors.affiliation: Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Peter J
authors.identifier: 0000-0001-8450-3518
authors.initials: PJ
authors.lastname: van der Most
authors.affiliation: Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Behrooz Z
authors.identifier: 0000-0002-1415-8007
authors.initials: BZ
authors.lastname: Alizadeh
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.|Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Paul Iw
authors.initials: PI
authors.lastname: de Bakker
authors.affiliation: Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: H Marike
authors.initials: HM
authors.lastname: Boezen
authors.affiliation: Lifelines Cohort Study, Groningen, The Netherlands.
authors.forename: Marcel
authors.initials: M
authors.lastname: Bruinenberg
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Department of Cardiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Pim
authors.initials: P
authors.lastname: van der Harst
authors.affiliation: Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Gerjan
authors.initials: G
authors.lastname: Navis
authors.affiliation: Department of Pulmonology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dirkje S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Department of Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Marianne G
authors.initials: MG
authors.lastname: Rots
authors.affiliation: Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Ronald P
authors.initials: RP
authors.lastname: Stolk
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Morris A
authors.initials: MA
authors.lastname: Swertz
authors.affiliation: Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Bruce Hr
authors.initials: BH
authors.lastname: Wolffenbuttel
authors.affiliation: Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Cisca
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Unit of Genetic Epidemiology and Bioinformatics, Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Harold
authors.initials: H
authors.lastname: Snieder
mesh_terms: D001772:Blood Cell Count; D001794:Blood Pressure / Q000235:genetics; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods* / Q000592:standards; D006339:Heart Rate / Q000235:genetics; D006801:Humans; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012119:Respiration / Q000235:genetics