Abstract
Background
SNP-based heritability is a fundamental quantity in the genetic analysis of complex
traits. For case-control phenotypes, for which the continuous distribution of risk
in the population is unobserved, observed-scale heritability estimates must be transformed
to the more interpretable liability scale. The current paper describes how the field
standard approach incorrectly performs the liability correction in that it does not
appropriately account for variation in the proportion of cases across the cohorts
comprising the meta-analysis. We propose a simple solution that incorporates cohort-specific
ascertainment using the summation of effective sample sizes across cohorts. This solution
is applied at the stage of SNP-based heritability estimation and does not require
generating updated meta-analytic GWAS summary statistics.
Methods
We begin by performing a series of simulations to examine the ability of the standard
approach and our proposed approach to recapture liability-scale heritability in the
population. We go on to examine the differences in estimates obtained from these two
approaches for real data for 12 major case-control GWAS of psychiatric and neurological
traits.
Results
We find that the field standard approach for performing the liability conversion can
downwardly bias estimates by as much as ∼50% in simulation and ∼30% in real data.
Conclusions
Prior estimates of liability scale heritability for GWAS meta-analysis may be drastically
underestimated. To this end, we strongly recommend using our proposed approach of
using the sum of effective sample sizes across contributing cohorts in order to obtain
unbiased estimates.
Keywords
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Article Info
Publication History
Accepted:
May 21,
2022
Received in revised form:
May 2,
2022
Received:
September 27,
2021
Publication stage
In Press Journal Pre-ProofFootnotes
1 We note that we have observed different, statistically equivalent versions of calculating effective sample size in the literature, any of which may be used so long as they are calculated at the cohort-level prior to summation. At the cohort-specific level, these equivalent versions can be expressed as either: .
Identification
Copyright
© 2022 Society of Biological Psychiatry.
