LDSC
I applied Linkage Disequlibirum Score Regression1 to the GWAS of chronic fatigue syndrome (CFS) performed as part of the Million Veterans Program2. Note that while DecodeME3 used a carefully constructed case definition, Million Veterans GWAS are based on PheCodes, which are aggregations of billing codes. We can thus expect that the Million Veterans GWAS may be significantly more noisy than DecodeME.
The results of running LDSC are listed below:
| Parameter | Value |
|---|---|
| h2_liab | 0.03316 |
| h2_liab_se | 0.01238 |
| Lambda_gc | 1.037 |
| Mean_chi2 | 1.034 |
| Intercept | 1.013 |
| Intercept_se | 0.005807 |
| Ratio | 0.3861 |
| Ratio_se | 0.171 |
Notably, the liability scale heritability is less than half that found in the analogous DecodeME analysis.
While the LDSC intercept is low, so is the mean \(\chi^2\) statistic. Consequently, the attenuation ratio is moderate-to-high. This suggests some possibility of confounding by stratification.
Due to the low number of cases, the quantities in the table above have relatively high standard errors.
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Brendan K Bulik-Sullivan, Po-Ru Loh, Hilary K Finucane, Stephan Ripke, Jian Yang, Nick Patterson, Mark J Daly, Alkes L Price, and Benjamin M Neale. LD Score regression distinguishes confounding from polygenicity in genome-wide association studies. Nature Genetics, 47(3):291–295, 2015. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC4495769/. ↩
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Anurag Verma, Jennifer E Huffman, Alex Rodriguez, Mitchell Conery, Molei Liu, Yuk-Lam Ho, Youngdae Kim, David A Heise, Lindsay Guare, Vidul Ayakulangara Panickan, and others. Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program. Science, 385(6706):eadj1182, 2024. URL: https://www.science.org/doi/10.1126/science.adj1182. ↩
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Genetics Delivery Team, Thibaud Boutin, Andrew D Bretherick, Joshua J Dibble, Esther Ewaoluwagbemiga, Emma Northwood, Gemma L Samms, Veronique Vitart, Project, Cohort Delivery Team, Øyvind Almelid, and others. Initial findings from the DecodeME genome-wide association study of myalgic encephalomyelitis/chronic fatigue syndrome. medRxiv, pages 2025–08, 2025. URL: https://www.medrxiv.org/content/10.1101/2025.08.06.25333109v1. ↩