NERINE reveals rare variant associations in gene networks across phenotypes and implicates an SNCA-PRL-LRRK2 subnetwork in Parkinson’s disease

There are two primary approaches to study the genetic basis of human phenotypes. Experiments in model systems generate interpretable gene networks but, in isolation, do not establish relevance to the human condition. Statistical genetics identifies relevant association signals at the variant or gene level but lacks tools to test specific mechanistic models, as existing methods do not incorporate the topology of gene-gene interactions. We bridge these two strategies by introducing a method that competitively tests network hypotheses with rare variant associations. A hierarchical model-based association test NERINE for the first time incorporates gene network topology while remaining resilient to network inaccuracies. We demonstrate NERINE’s ability to test network hypotheses derived from both canonical pathway databases and model system screens. Comprehensive database-wide search of pathway networks with NERINE uncovers compelling associations for breast cancer, cardiovascular diseases, and type II diabetes, which are undetected by single-gene tests. Testing bespoke networks from experimental screens targeting key PD pathologies: dopaminergic neuron survival and α-synuclein pathobiology, NERINE highlights rare variant burden in gene modules related to autophagy, vesicle trafficking, and protein homeostasis. Genome-scale CRISPRi-screening of α-synuclein toxicity modifiers in human neurons and NERINE converge on PRL , revealing an intraneuronal α-synuclein / prolactin stress response that may impact resilience to PD pathologies.