Chr1 173.5M-174.5M
Methodology
To narrow the DecodeME1 GWAS-1 signal, I fine-mapped the hit on chromosome 1 using SUSIE2.
As a linkage disequilibrium reference, I used a UK Biobank LD matrix hosted on AWS Open Data. Because this LD reference uses GRCh37 coordinates, I used GWASLab to liftover the DecodeME summary statistics to GRCh37.
As a sensitivity analysis, I ran SUSIE 4 times:
- Once with \(L=10\),
- Once with \(L=2\),
- Once with \(L=1\),
- Once with \(L=10\) and strict variant filtering.
\(L\) refers to the maximum number of credible sets that can found by SUSIE. A lower \(L\) corresponds to increased regularization, since it decreases the ability of SUSIE to use extra credible sets to fit noise. Weissbrod et al.3 observe that setting \(L\) to 1 protects against mismatch between the LD reference population and the GWAS population, because when \(L=1\), SUSIE no longer depends on the LD matrix. They also observe that when \(L=2\), even though SUSIE still depends on the LD matrix, empirically it tends to be robust to moderate levels of population mismatch. I thus used the \(L=1\) and \(L=2\) runs to evaluate whether population mismatch could be influencing SUSIE's results.
"Variant filtering" refers to removal of outlier variants according to a Kriging-based likelihood ratio test. Zou et al.4 propose this filtering strategy to mitigate instability in SUSIE due to mismatch between the LD and GWAS populations. In the first three runs above, I filter variants with a likelihood ratio (\(\mathrm{LR}\)) and absolute \(z\) score greater than 2, consistent with the SUSIE documentation. In the final run I instead filter variants with \(\mathrm{LR}\ge 2\) and \(|z|\ge 1\), to evaluate the sensitivity of the results to the filtering threshold.
In my SUSIE runs, I retained palindromic SNPs whose strand orientation GWASLAB was able to determine from allele frequencies in the Thousand Genomes Project, and discarded other palindromic SNPs.
Results
In all 4 runs, SUSIE found a single diffuse credible set. Moreover, this credible set contained the same 86 variants in all four runs, as illustrated in the UpSet plot below:
The next figure illustrates the SUSIE results for \(L=10\). It is representative of the other runs.
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The top panel is a heatmap in which pixel \((i,j)\) is colored according to the squared correlation between variants \(i\) and \(j\). The heatmap reveals the local linkage disequilibrium (LD) structure in the vicinity of the GWAS hit, which is a determinant of SUSIE's results when \(L>1\).
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The second panel shows a local Manhattan plot.
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The third panel shows the SUSIE posterior inclusion probability (PIP).
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The bottom panel shows genes in the region of the GWAS hit.
Overall, SUSIE has returned a diffuse signal in a region with a number of plausible genes. This makes it unclear which genes deserve follow-up investigation.
The table below lists the full detailed SUSIE results for the \(L=10\) case
Variant List
| cs | CHR | POS | EA | NEA | alpha | mu | PIP |
|---|---|---|---|---|---|---|---|
| L1 | 1 | 173815290 | C | T | 0.0349532 | -0.022181 | 0.0349532 |
| L1 | 1 | 173853127 | C | T | 0.0334384 | -0.0221481 | 0.0334384 |
| L1 | 1 | 173865586 | T | C | 0.0332454 | -0.0221439 | 0.0332454 |
| L1 | 1 | 173815111 | C | T | 0.0332354 | -0.0221436 | 0.0332354 |
| L1 | 1 | 173866074 | A | T | 0.0332311 | -0.0221435 | 0.0332311 |
| L1 | 1 | 173878862 | C | T | 0.0328582 | -0.0221352 | 0.0328582 |
| L1 | 1 | 173812639 | A | C | 0.0327682 | -0.0221331 | 0.0327682 |
| L1 | 1 | 173851310 | A | G | 0.0313245 | -0.0220996 | 0.0313245 |
| L1 | 1 | 173859100 | G | A | 0.0296411 | -0.0220585 | 0.0296411 |
| L1 | 1 | 173863209 | A | G | 0.0296014 | -0.0220575 | 0.0296014 |
| L1 | 1 | 173863569 | A | T | 0.0292311 | -0.0220482 | 0.0292311 |
| L1 | 1 | 173863567 | T | G | 0.0292311 | -0.0220482 | 0.0292311 |
| L1 | 1 | 173846590 | G | T | 0.0276321 | -0.0220062 | 0.0276321 |
| L1 | 1 | 173863568 | T | A | 0.0275657 | -0.0220044 | 0.0275657 |
| L1 | 1 | 173832336 | T | C | 0.0272003 | -0.0219944 | 0.0272003 |
| L1 | 1 | 173878832 | C | T | 0.0261331 | -0.0219645 | 0.0261331 |
| L1 | 1 | 173838788 | T | TG | 0.0261228 | -0.0219642 | 0.0261228 |
| L1 | 1 | 173855298 | T | A | 0.0255997 | -0.0219491 | 0.0255997 |
| L1 | 1 | 173846110 | A | G | 0.025353 | -0.0219418 | 0.025353 |
| L1 | 1 | 173857283 | G | A | 0.0243066 | -0.0219102 | 0.0243066 |
| L1 | 1 | 173848009 | G | A | 0.023978 | -0.0219 | 0.023978 |
| L1 | 1 | 173824813 | T | C | 0.0234489 | -0.0218833 | 0.0234489 |
| L1 | 1 | 173842467 | G | A | 0.0230966 | -0.0218719 | 0.0230966 |
| L1 | 1 | 173870321 | G | GTAC | 0.0230538 | -0.0218705 | 0.0230538 |
| L1 | 1 | 173857037 | T | C | 0.0228147 | -0.0218627 | 0.0228147 |
| L1 | 1 | 173881871 | T | C | 0.0203149 | -0.0217753 | 0.0203149 |
| L1 | 1 | 173844051 | T | A | 0.0184477 | -0.0217024 | 0.0184477 |
| L1 | 1 | 173820365 | C | T | 0.0145082 | -0.0215198 | 0.0145082 |
| L1 | 1 | 173832772 | CA | C | 0.0144368 | -0.021516 | 0.0144368 |
| L1 | 1 | 173878471 | G | A | 0.0118415 | -0.0213641 | 0.0118415 |
| L1 | 1 | 173831882 | G | A | 0.00912575 | -0.0211628 | 0.00912575 |
| L1 | 1 | 173743879 | CAAAA | C | 0.00696391 | -0.0209519 | 0.00696391 |
| L1 | 1 | 173717200 | ACT | A | 0.00675049 | -0.0209275 | 0.00675049 |
| L1 | 1 | 173767443 | T | A | 0.00660937 | -0.0209109 | 0.00660937 |
| L1 | 1 | 173783493 | C | T | 0.00650478 | -0.0208983 | 0.00650478 |
| L1 | 1 | 173699007 | G | A | 0.00592378 | -0.0208246 | 0.00592378 |
| L1 | 1 | 173698510 | T | C | 0.00585287 | -0.0208151 | 0.00585287 |
| L1 | 1 | 173709616 | G | T | 0.0056909 | -0.020793 | 0.0056909 |
| L1 | 1 | 173734270 | CAACA | C | 0.0056717 | -0.0207903 | 0.0056717 |
| L1 | 1 | 173683954 | T | C | 0.00516697 | -0.0207165 | 0.00516697 |
| L1 | 1 | 173755936 | TGAAG | T | 0.00476139 | -0.0206516 | 0.00476139 |
| L1 | 1 | 174210076 | T | TTG | 0.00289739 | -0.0202525 | 0.00289739 |
| L1 | 1 | 174128994 | G | A | 0.00239407 | -0.0200971 | 0.00239407 |
| L1 | 1 | 174158856 | C | T | 0.00235282 | -0.0200829 | 0.00235282 |
| L1 | 1 | 174111115 | T | C | 0.00229859 | -0.0200638 | 0.00229859 |
| L1 | 1 | 174066947 | T | C | 0.00227798 | -0.0200564 | 0.00227798 |
| L1 | 1 | 174069469 | CT | C | 0.00227531 | -0.0200555 | 0.00227531 |
| L1 | 1 | 174084104 | A | G | 0.0022655 | -0.0200519 | 0.0022655 |
| L1 | 1 | 174152688 | G | A | 0.00225032 | -0.0200464 | 0.00225032 |
| L1 | 1 | 174146656 | C | A | 0.00222885 | -0.0200385 | 0.00222885 |
| L1 | 1 | 174085043 | TACA | T | 0.00219654 | -0.0200266 | 0.00219654 |
| L1 | 1 | 174076864 | C | G | 0.00218651 | -0.0200228 | 0.00218651 |
| L1 | 1 | 174064481 | A | T | 0.0021761 | -0.0200189 | 0.0021761 |
| L1 | 1 | 174068049 | A | G | 0.00215682 | -0.0200116 | 0.00215682 |
| L1 | 1 | 174069981 | C | T | 0.00215307 | -0.0200102 | 0.00215307 |
| L1 | 1 | 174191694 | C | T | 0.00214725 | -0.0200079 | 0.00214725 |
| L1 | 1 | 174062911 | C | T | 0.00214307 | -0.0200063 | 0.00214307 |
| L1 | 1 | 174057626 | T | C | 0.00214136 | -0.0200057 | 0.00214136 |
| L1 | 1 | 174241165 | C | G | 0.0021385 | -0.0200046 | 0.0021385 |
| L1 | 1 | 174093837 | G | T | 0.00213651 | -0.0200038 | 0.00213651 |
| L1 | 1 | 174157834 | A | G | 0.00213405 | -0.0200029 | 0.00213405 |
| L1 | 1 | 174170341 | C | T | 0.00213381 | -0.0200028 | 0.00213381 |
| L1 | 1 | 174086292 | T | C | 0.00211439 | -0.0199953 | 0.00211439 |
| L1 | 1 | 174050667 | G | A | 0.00210878 | -0.0199931 | 0.00210878 |
| L1 | 1 | 174068929 | A | G | 0.00207848 | -0.0199812 | 0.00207848 |
| L1 | 1 | 174079700 | G | C | 0.00207189 | -0.0199786 | 0.00207189 |
| L1 | 1 | 174118271 | C | G | 0.00206586 | -0.0199762 | 0.00206586 |
| L1 | 1 | 174075924 | G | T | 0.00206197 | -0.0199746 | 0.00206197 |
| L1 | 1 | 174075925 | C | T | 0.00206197 | -0.0199746 | 0.00206197 |
| L1 | 1 | 174059522 | C | G | 0.002049 | -0.0199694 | 0.002049 |
| L1 | 1 | 174161430 | A | G | 0.00203663 | -0.0199645 | 0.00203663 |
| L1 | 1 | 174072203 | G | A | 0.00203588 | -0.0199642 | 0.00203588 |
| L1 | 1 | 174078417 | A | G | 0.00202943 | -0.0199615 | 0.00202943 |
| L1 | 1 | 174079584 | T | A | 0.00202752 | -0.0199608 | 0.00202752 |
| L1 | 1 | 174079585 | G | A | 0.00202752 | -0.0199608 | 0.00202752 |
| L1 | 1 | 174069421 | T | C | 0.00191843 | -0.0199152 | 0.00191843 |
| L1 | 1 | 174176363 | G | A | 0.00190403 | -0.019909 | 0.00190403 |
| L1 | 1 | 174144293 | CACAT | C | 0.00189623 | -0.0199056 | 0.00189623 |
| L1 | 1 | 174197408 | G | A | 0.00187952 | -0.0198983 | 0.00187952 |
| L1 | 1 | 174078860 | C | T | 0.00187677 | -0.0198971 | 0.00187677 |
| L1 | 1 | 174113408 | G | A | 0.0018707 | -0.0198944 | 0.0018707 |
| L1 | 1 | 174152476 | C | T | 0.0018538 | -0.0198869 | 0.0018538 |
| L1 | 1 | 174150850 | C | T | 0.00182508 | -0.019874 | 0.00182508 |
| L1 | 1 | 174060062 | G | A | 0.00180084 | -0.0198629 | 0.00180084 |
| L1 | 1 | 174326702 | G | A | 0.00161599 | -0.0197731 | 0.00161599 |
| L1 | 1 | 174288602 | G | A | 0.00158912 | -0.0197592 | 0.00158912 |
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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. ↩
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Omer Weissbrod, Farhad Hormozdiari, Christian Benner, Ran Cui, Jacob Ulirsch, Steven Gazal, Armin P Schoech, Bryce Van De Geijn, Yakir Reshef, Carla Márquez-Luna, and others. Functionally informed fine-mapping and polygenic localization of complex trait heritability. Nature Genetics, 52(12):1355–1363, 2020. URL: https://pmc.ncbi.nlm.nih.gov/articles/PMC7710571/. ↩
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Yuxin Zou, Peter Carbonetto, Gao Wang, and Matthew Stephens. Fine-mapping from summary data with the “Sum of Single Effects” model. PLoS Genetics, 18(7):e1010299, 2022. URL: https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010299. ↩