Does polygenic risk for substance-related traits predict ages of onset and progression of symptoms?

BACKGROUND AND AIMS: Genetic risk can influence disease progression. We measured the impact of genetic risk for substance use disorders (SUDs) on substance use onset and progression of symptoms. DESIGN, SETTING, PARTICIPANTS: Using findings from genome-wide association studies (GWASs) of alcohol use disorder (AUD), opioid use disorder (OUD) and smoking trajectory (SMK) as discovery samples, we calculated polygenic risk scores (PRSs) in a deeply phenotyped independent target sample. Participants in the target sample were recruited from 2000 to 2020 from US inpatient or outpatient settings or through advertisements and comprised 5692 European-ancestry individuals (EUR) (56.2% male) and 4918 African-ancestry individuals (AFR) (54.9% male). MEASUREMENTS: This study measured age of first substance use, regular use, reported problems and dependence diagnosis and progression from regular use to onset of problems and dependence for alcohol, opioids and smoking. We examined the contribution of PRS to each milestone and progression measure. FINDINGS: EUR and males reported an earlier onset and shorter progression times than AFR and females, respectively. Among EUR, higher AUD PRS predicted earlier onset and more rapid progression to alcohol-related milestones (P < 0.001). Although the AUD PRS was a stronger moderator of problem onset among females (P = 0.017), it was more predictive of the progression to problems among males (P = 0.005). OUD and SMK PRS in EUR also predicted earlier onset of the respective milestones (P < 0.001). Among AFR, where power is lower due to the smaller discovery sample, AUD PRS predicted age of regular alcohol use (P = 0.039) and dependence (P = 0.001) and progression from regular use to diagnosis (P = 0.045), while SMK PRS predicted earlier age of initiation (P = 0.036). CONCLUSIONS: Genetic risk for SUDs appears to predict substance use milestones and symptom progression among European-ancestry individuals and, to a lesser extent, African-ancestry individuals.

NRG/ErbB signaling regulates neonatal muscle growth but not neuromuscular contractures in neonatal brachial plexus injury.

Neonatal brachial plexus injury (NBPI) causes disabling and incurable muscle contractures that are driven by impaired growth of denervated muscles. A rare form of NBPI, which maintains afferent muscle innervation despite motor denervation, does not cause contractures. As afferent innervation regulates various aspects of skeletal muscle homeostasis through NRG/ErbB signaling, our current study investigated the role of this pathway in modulating contracture development. Through pharmacologic modification with an ErbB antagonist and NRG1 isoforms, we discovered that NRG/ErbB signaling does not modulate the development of contractures in neonatal mice. Instead, ErbB inhibition impeded growth in nondenervated skeletal muscles, whereas increased ErbB activation exacerbated denervation-induced skeletal muscle atrophy. This potential regulatory effect of NRG/ErbB signaling on neonatal muscle growth warrants deeper investigation.