SynthesisBiological psychiatry2023
Pervasive Downward Bias in Estimates of Liability-Scale Heritability in Genome-wide Association Study Meta-analysis: A Simple Solution.
Synthesis in Biological psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers, 6 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
71 citing papers in PubMed, 6 syntheses or guidelines pooled it.
- Genome-wide association analyses of borderline personality disorder identify 11 loci and highlight shared risk with mental and somatic disorders.Nature genetics · 2026Pooled it
- Deciphering the shared genetic architecture between schizophrenia and suicide attempt: a statistical genomic study.BMC psychiatry · 2026Pooled it
- Genome-wide association study of major anxiety disorders in 122,341 European-ancestry cases identifies 58 loci and highlights GABAergic signaling.Nature genetics · 2026Pooled it
- Genome-wide analyses identify 30 loci associated with obsessive-compulsive disorder.Nature genetics · 2025Pooled it
- Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes.Nature genetics · 2025Pooled it
- GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture.Nature genetics · 2023Pooled it
- Multivariate genetic analyses test for the presence of a general 'JCPP advances · 2026Article
- Genetic architectures of brain-related traits are shaped by strong selective constraints.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Immune markers mediate genetic relationships between immune diseases and psychiatric disorders.PLoS genetics · 2026Article
- Distinguishing different psychiatric disorders using DDx-PRS.Nature genetics · 2026Article
- Uncovering the Role of Biological Sex in the Divergent Genetic Profiles of Early and Late-Diagnosed Autism.Behavior genetics · 2026Article
- Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.Research square · 2026Article
- The genetic architecture of fibromyalgia across 2.5 million individuals.Nature medicine · 2026Article
- Molecular genetic influences on sustained attention and executive processes and their links with psychopathology in the AFFECT study.Molecular psychiatry · 2026Article
- Genome-wide genetic overlap between fear-based disorders and generalised anxiety disorder.Molecular psychiatry · 2026Article
- Mapping the genetic architecture of human cortical expansion and its links to neuropsychiatric disorders.bioRxiv : the preprint server for biology · 2026Article
- Sex-biased Genetic Risk Loci and Causal Brain Proteins in Parkinson's Disease.medRxiv : the preprint server for health sciences · 2026Article
- Ultra-Fast Implementation of Multivariate GWAS in Genomic SEM Using Flexible Analytic Estimation.bioRxiv : the preprint server for biology · 2026Article
- APOE*4 risk-modifying genes and drug targets in Alzheimer's disease through cell-type-specific genomic analyses.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026Article
- UK Biobank at 20 - a growing, global resource for dementia research.Nature reviews. Neurology · 2026Review
11 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors.
Funding
Abstract
backgroundSingle nucleotide polymorphism-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. This article 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 single nucleotide polymorphism-based heritability estimation and does not require generating updated meta-analytic genome-wide association study summary statistics.
methodsWe began 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 went on to examine the differences in estimates obtained from these 2 approaches for real data for 12 major case-control genome-wide association studies of psychiatric and neurologic traits.
resultsWe found that the field standard approach for performing the liability conversion can downwardly bias estimates by as much as approximately 50% in simulation and approximately 30% in real data.
conclusionsPrior estimates of liability-scale heritability for genome-wide association study 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 to obtain unbiased estimates.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.