AyurPhenoClusters define common molecular roots for rare diseases and uncover ciliary dysfunctions in syndromic conditions

Abstract

Managing rare genetic diseases with organ centric focus presents a challenge in linking genotypes to phenotypic traits. Ayurveda on the other hand, diagnose diseases with multi-system perspective that are assessed by perturbations along three physiological dimensions viz- kinetic (Vata), metabolic (Pitta) and structural (Kapha) each with distinct phenotypic attributes and molecular correlates. This study explores how rare diseases, can be viewed from an Ayurvedic perspective by unifying the medical terminologies from both disciplines through Human Phenotype Ontology (HPO). Domain experts categorized 10,610 HPO terms into phenotypic groups based on Ayurvedic principles of Vata (V), Pitta (P), and Kapha (K) and used the Expectation Maximization (EM) algorithm to cluster and analyze 12,678 diseases. This revealed six distinct clusters collectively called "AyurPhenoClusters". 2814 diseases had unique memberships to single clusters showing enrichment for V/P/K phenotypes. Clusterwise functional annotation revealed the top processes as (i) embryogenesis and skeletal system, morphogenesis; (ii) endocrine and ciliary functions (iii) DNA damage response and cell cycle regulation (iv) inflammation and immune response (v) immune, hemopoiesis, telomere aging (vi) Small molecule metabolism and transport. Most noteworthy, K predominant cluster was significantly enriched for ciliary genes (43%) followed by a V predominant cluster (16 %). Our study also suggests that many rare diseases especially in the V cluster could be potential ciliopathies. This first of its kind of study provides an innovative framework that can bridge the gap between Ayurveda and modern medicine for improved mechanistic understanding of the rare diseases and pave the way for improved diagnostic and therapeutic strategies.