Heritability and genetic correlation analyses

For estimates of heritability and genetic correlations we used the LDSC toolbox created by Bulik et al.¹. In order to estimate the SNP heritability, the LDSC toolbox uses partitioned heritability estimates that take into account the LD structure of the genome which allows it to improve power by using all SNPs in a sample rather than just the single causal SNP per locus². To calculate heritability the LDSC toolbox combines the GWAS summary statistics with a reference panel of the LD structure from a population with the same or similar ancestry. In order to get reliable estimates, we transformed the effect sizes for each SNP into z-scores and excluded the MHC region prior to running our analyses.

Genetic correlation is a measure of the shared genetic effects between two phenotypes. To quantify the genetic correlation between two traits the LDSC toolbox uses LD score regression (r_g) on the effect sizes of all individual SNPs, while also considering the effects of all SNPs in LD with a given SNP³. LD score regression is indifferent to sample overlap. Sample overlap introduces non-random correlations in the model, but these correlations are uniformly distributed across the markers and not tied to LD structure. As a consequence, sample overlap only affects the intercept but not the slope of the regression³. As such, the LDSC toolbox can calculate the genetic correlation with just the GWAS summary statistics and a LD reference panel for that population and is indifferent.

1.

Bulik-Sullivan BK, Loh PR, Finucane HK, Ripke S, Yang J, Patterson N, et al. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nature Genetics [Internet]. 2015 Mar 1;47(3):291–5. Available from: https://doi.org/10.1038/ng.3211

2.

Finucane HK, Bulik-Sullivan B, Gusev A, Trynka G, Reshef Y, Loh PR, et al. Partitioning heritability by functional annotation using genome-wide association summary statistics. Nature Genetics [Internet]. 2015 Nov 1;47(11):1228–35. Available from: https://doi.org/10.1038/ng.3404

3.

Bulik-Sullivan B, Finucane HK, Anttila V, Gusev A, Day FR, Loh PR, et al. An atlas of genetic correlations across human diseases and traits. Nature Genetics [Internet]. 2015 Nov 1;47(11):1236–41. Available from: https://doi.org/10.1038/ng.3406