COMPREHENSIVE GENETIC INVESTIGATION REVEALS HETEROGENEOUS PATHWAYS TO OBSTRUCTIVE SLEEP APNEA

Anne E. Justice; Brendan T Keenan; Geetha Chittoor; Matthew C. Pahl; Hanne Hoskens; Navya Shilpa Josyula; Shreyash Gupta; Soriul Kim; Guðmar Þorleifsson; Elisabetta Manduchi; Alejandro Gutierrez; Fernando Andrade; Cheryl L. Ackert‐Bicknell; Bryndis Benediktsdottir; Jaime Boero; Kenneth M. Borthwick; N. Chen; Peter A. Cistulli; Lacey J. Favazzo; Daniel J. Gottlieb; Hakon H. Hakonarson; Henry Lester Kirchner; Ulysses J. Magalang; Beth Ann Malow; Diego R Mazzotti; Nigel McArdle; Frank D. Mentch; Timothy I. Morgenthaler; Thomas Penzel; James A. Pippin

doi:10.64898/2026.01.08.26343696

Genetic & Genomic MedicinemedRxivJan 11, 2026

Preprint

COMPREHENSIVE GENETIC INVESTIGATION REVEALS HETEROGENEOUS PATHWAYS TO OBSTRUCTIVE SLEEP APNEA

Anne E. Justice iD, Brendan T Keenan iD, Geetha Chittoor iD, Matthew C. Pahl iD, Hanne Hoskens iD, Navya Shilpa Josyula iD, Shreyash Gupta iD, Soriul Kim iD, Guðmar Þorleifsson iD, Elisabetta Manduchi iD, Alejandro Gutierrez iD, Fernando Andrade iD, Cheryl L. Ackert‐Bicknell iD, Bryndis Benediktsdottir, Jaime Boero, Kenneth M. Borthwick, N. Chen, Peter A. Cistulli iD, Lacey J. Favazzo iD, Daniel J. Gottlieb iD, Hakon H. Hakonarson iD, Henry Lester Kirchner iD, Ulysses J. Magalang iD, Beth Ann Malow iD, Diego R Mazzotti iD, , Allan I Pack iD

Abstract

Obstructive sleep apnea (OSA) is a common, heritable disorder with diverse clinical presentations and etiologies. We conducted a genome-wide association meta-analysis of 492,107 individuals, including 46,028 OSA cases, identifying 14 genome-wide significant loci, eight of which are novel. Analyses adjusting for body mass index (BMI) revealed three loci independent of obesity, implicating alternative biological pathways contributing to disease. Integrative functional analyses, including chromatin interaction mapping, fine-mapping, and eQTL colocalization, prioritized candidate effector genes. Notably, implicated genes in chondrocytes were associated with craniofacial morphology in both mouse and human multivariate genotype-phenotype mapping, supporting a role for craniofacial structure in OSA risk. These findings highlight key genetic pathways (obesity-related, neurological, and craniofacial) underlying the development of OSA, offering new insights into its complex etiology.

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