Missing Heritability: Is the Gap Closing? an Analysis of 32 Complex Traits in the Lifelines

Missing heritability: is the gap closing? An analysis of 32 complex traits in the LifeLines Cohort Study.

Ilja M Nolte (1), Peter J van der Most (1), Behrooz Z Alizadeh (1), Paul de Bakker (2,3), H Marike Boezen (1), Marcel Bruinenberg (4), Lude Franke (5) Pim van der Harst (6), Gerjan Navis (7), Dirkje S Postma (8), Marianne Rots (9), Ronald P Stolk (1,4), Morris Swertz (5), Bruce HR Wolffenbuttel (10), Cisca Wijmenga (5), Harold Snieder (1)

(1) Department of Epidemiology, University of Groningen, University Medical Center Groningen, The Netherlands

(2) Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, The Netherlands

(3) Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands

(4) LifeLines Cohort Study, University of Groningen, University Medical Center Groningen, The Netherlands

(5) Department of Genetics, University of Groningen, University Medical Center Groningen, The Netherlands

(6) Department of Cardiology, University of Groningen, University Medical Center Groningen, The Netherlands

(7) Department of Nephrology, University of Groningen, University Medical Center Groningen, The Netherlands

(8) Department of Pulmonology, University of Groningen, University Medical Center Groningen, The Netherlands

(9) Department of Medical Biology, University of Groningen, University Medical Center Groningen, The Netherlands

(10) Department of Endocrinology, University of Groningen, University Medical Center Groningen, The Netherlands

Abstract (1497 characters excluding spaces [max 1500])

In recent years, thousands of genetic variants have been identified by genome-wide association studies as associated with various complex traits and diseases, but they often explain only a small part of the variance. Recently, a new method was proposed to determine the proportion of dominance genetic variance at all common SNPs, which might explain part of the missing heritability.

In this study, we selected 1,442 single nucleotide polymorphisms (SNPs) that were genome-wide significantly associated with 32 continuous traits from five disease areas (musculoskeletal, cardiovascular/renal, metabolic, haematologic/inflammatory, and pulmonary). We used 13,436 subjects from the LifeLines Cohort Study, a population-based prospective cohort examining the health of 167,729 persons from the northern Netherlands, to estimate the proportions of phenotypic variance that could be attributed to additive and dominance genetic variance at all common SNPs and to perform replication analyses and to calculate the percentage of phenotypic variance explained by all associated SNPs combined in genetic risk scores (GRSs).

The additive genetic variance at all common SNP explained a significant proportion of the phenotypic variance for all traits ranging from 7.5% to 52.2%, but none of the traits showed significant dominance variance. A total of 66.0% of all high-quality SNPs were significantly associated with the trait of interest and all GRSs composed of known SNPs associated significantly with their respective trait with variances explained between 0.02% and 15.5%. In conclusion, a considerable part of the common SNP heritability for complex disease traits remains to be explained and detected. Such variants will have mostly additive effects.