Preprint Actively Protective Combinatorial Analysis: a Scalable Novel Method for Detecting Variants that Contribute to Reduced Disease…, 2025, Sardell+

Actively Protective Combinatorial Analysis: a Scalable Novel Method for Detecting Variants that Contribute to Reduced Disease Prevalence in High-Risk Individuals
Jason Sardell; Sayoni Das; Krystyna Taylor; Colin Stubberfield; Andy Malinowski; Mark Strivens; Steve Gardner

We present a novel method for routinely identifying disease resilience associations that offers powerful insights for the discovery of a new class of disease protective targets. We show how this can be used to identify mechanisms in the background of normal cellular biology that work to slow or stop progression of complex, chronic diseases.

Actively protective combinatorial analysis identifies combinations of features that contribute to reducing risk of disease in individuals who remain healthy even though their genomic profile suggests that they have high risk of developing disease. These protective signatures can potentially be used to identify novel drug targets, pharmacogenomic and/or therapeutic mRNA opportunities and to better stratify patients by overall disease risk and mechanistic subtype.

We describe the method and illustrate how it offers increased power for detecting disease-associated genetic variants relative to traditional methods. We exemplify this by identifying individuals who remain healthy despite possessing several disease signatures associated with increased risk of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) or amyotrophic lateral sclerosis (ALS). We then identify combinations of SNP-genotypes significantly associated with reduced disease prevalence in these high-risk protected cohorts.

We discuss how actively protective combinatorial analysis generates novel insights into the genetic drivers of established disease biology and detects gene-disease associations missed by standard statistical approaches such as meta-GWAS. The results support the mechanism of action hypotheses identified in our original causative disease analyses. They also illustrate the potential for development of precision medicine approaches that can increase healthspan by reducing the progression of disease.


Link | PDF (Preprint: MedRxiv) [Open Access]

 

There's a disease signature? I'm intrigued. The rest of the paper looks really interesting, but for now I've only looked at the part about this.

It seems to say a gene was significant in three studies. The following two, and I'm not sure what the third one is because the citation number is wrong. Anyone know what the gene is they're talking about?

28. Genetic Risk Factors for ME/CFS Identified using Combinatorial Analysis, 2022, Das et al
29. Genetic variants associated with chronic fatigue syndrome predict population-level fatigue severity and actigraphic measurements, 2024, Liu et al.

 

S4ME thread for Genetic risk factors for ME/CFS identified using combinatorial analysis (2022, Journal of Translational Medicine)

 

Not sure if this is the right third study, but it's another genetic study:
Genetic Risk Factors for Severe and Fatigue Dominant Long COVID and Commonalities with ME/CFS Identified by Combinatorial Analysis, 2023, Taylor et al

Quickly looking at the three studies, it looks like ATP9A was highlighted in all of them. Though both the 2022 and 2024 studies used UK Biobank data. Were they the same individuals?

From the 2024 study:

Edit: Maybe it's UK Biobank in all three? Not sure.

 

Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies novel methylation loci, 2019, Smith et al (Preprint)

Using the Coriell Personalized Medicine Collaborative Data to conduct a genome-wide association study of sleep duration, 2015, Scheinfeldt et al (American Journal of Medical Genetics)

SA18 - ANALYSIS OF GENETIC VARIANTS IN MEXICAN CHILDREN WITH AUTISM SPECTRUM DISORDER: AN IMMUNGENOMIC APPROACH, 2019, Morales et al (European Neuropsychopharmacology)

Cross-Disorder Genome-Wide Analyses Suggest a Complex Genetic Relationship Between Tourette’s Syndrome and OCD, 2014, Yu et al (The American Journal of Psychiatry)
ATP9A was one of the highlighted genes, but none of the genes in the paper passed their threshold for significance.

Exome sequencing in bipolar disorder reveals shared risk gene AKAP11 with schizophrenia, 2022, Palmer et al (Nature Genetics) (Now published, but I took the quote from the preprint because it's paywalled.)

Homozygosity Haplotype and Whole-Exome Sequencing Analysis to Identify Potentially Functional Rare Variants Involved in Multiple Sclerosis among Sardinian Families, 2021, Fazia et al (Current Issues in Molecular Biology)

OMIM: Neurodevelopmental disorder with poor growth and behavioral abnormalities (NEDGBA)