Genome x Environment analysis of Sudden Unexpected Infant Death unveils etiologic heterogeneity and strong cannabis and genetic disease risks

Sudden Unexpected Infant Death (SUID), the third leading cause of infant death, has increasing incidence and multifactorial etiology. Identification of preventative interventions has hitherto been hindered by etiologic studies limited to genetic or environmental effects in isolation. Here we report a multifactorial genome x environment analysis of SUID risk. Births in San Diego County California from 2005-2018 were linked to hospital discharge summaries and death files, yielding 212 SUID cases and 620,392 infants alive at age 1 year. Whole genome sequencing (WGS) identified probable and possible genetic etiologies in 16% and 48% of SUID cases, respectively. Genetic risks were extremely heterogeneous with 144 loci contributing 173 risks in 57% of SUID cases. Genetic risk was very strong (Prevalence Risk Ratio, PRR >99) or strong (PRR 3.7 - 99) in 12% and 34% of SUID cases, respectively. Six of sixteen significant environmental risks lost significance when SUID cases without strong or very strong genetic risk were compared with infants alive at age 1 year, while SUID risk associated with prenatal cannabis increased from adjusted hazard ratio (aHR) 3.7 to 6.0, other substance abuse from aHR 2.6 to 3.5, and black race from aHR 1.9 to 2.5. Thus, genome x environment analysis of a large cohort unveiled etiologic heterogeneity and hidden SUID risks, highlighting cannabis and genetic diseases as strong risk factors. Since preventative or therapeutic interventions were available for 83% of genetic risks, newborn screening by WGS has potential for substantial SUID reduction. Educational campaigns for SUID should emphasize perinatal cannabis avoidance. One Sentence SummaryMultifactorial genome x environment analysis of a large cohort identified heterogeneous etiology in Sudden Unexpected Infant Death and unveiled strong risks from prenatal cannabis and genetic diseases.