Novel disease syndromes unveiled by integrative multiscale network analysis of diseases sharing molecular effectors and comorbidities

Background: Forty-two percent of patients experience disease comorbidity, contributing substantially to mortality rates and increased healthcare costs. Yet, the possibility of underlying shared mechanisms for diseases remains not well established, and few studies have confirmed their molecular predictions with clinical datasets. Methods: In this work, we integrated genome-wide association study (GWAS) associating diseases and single nucleotide polymorphisms (SNPs) with transcript regulatory activity from expression quantitative trait loci (eQTL). This allowed novel mechanistic insights for noncoding and intergenic regions. We then analyzed pairs of SNPs across diseases to identify shared molecular effectors robust to multiple test correction (False Discovery Rate FDR _eRNA < 0.05). We hypothesized that disease pairs found to be molecularly convergent would also be significantly overrepresented among comorbidities in clinical datasets. To assess our hypothesis, we used clinical claims datasets from the Healthcare Cost and Utilization Project (HCUP) and calculated significant disease comorbidities (FDR _comorbidity < 0.05). We finally verified if disease pairs resulting molecularly convergent were also statistically comorbid more than by chance using the Fisher's Exact Test. Results: Our approach integrates: (i) 6175 SNPs associated with 238 diseases from ~ 1000 GWAS, (ii) eQTL associations from 19 tissues, and (iii) claims data for 35 million patients from HCUP. Logistic regression (controlled for age, gender, and race) identified comorbidities in HCUP, while enrichment analyses identified cis- and trans-eQTL downstream effectors of GWAS-identified variants. Among ~ 16,000 combinations of diseases, 398 disease-pairs were prioritized by both convergent eQTL-genetics (RNA overlap enrichment, FDR _eRNA < 0.05) and clinical comorbidities (OR > 1.5, FDR _comorbidity < 0.05). Case studies of comorbidities illustrate specific convergent noncoding regulatory elements. An intergenic architecture of disease comorbidity was unveiled due to GWAS and eQTL-derived convergent mechanisms between distinct diseases being overrepresented among observed comorbidities in clinical datasets (OR = 8.6, p-value = 6.4 × 10 ^{- 5} FET). Conclusions: These comorbid diseases with convergent eQTL genetic mechanisms suggest clinical syndromes. While it took over a decade to confirm the genetic underpinning of the metabolic syndrome, this study is likely highlighting hundreds of new ones. Further, this knowledge may improve the clinical management of comorbidities with precision and shed light on novel approaches of drug repositioning or SNP-guided precision molecular therapy inclusive of intergenic risks.