Background: Speech-in-noise (SIN) deficits refer to difficulties understanding speech against background noise. A recent genome-wide association study (GWAS) revealed polygenic architecture underlying SIN deficits in individuals with self-reported normal hearing. The objective of the present study was to investigate the genetic comorbidities of SIN deficits. We employed a polygenic risk score (PRS)-based association analysis to identify genetic comorbidities of SIN deficits across the health phenome. PRS can quantify the risk of complex health traits based on the genetic predisposition to disease-associated variants.

Method: The PRS-based association analysis of SIN deficits was conducted on the UK Biobank cohort, followed by a replication analysis using clinical measures of SIN deficits in a cohort of healthy young adults with normal audiograms. The UK Biobank sample included 279,911 participants with 58,847 cases reporting SIN deficits with self-reported normal hearing in quiet and 221,067 controls without SIN deficits and reporting normal hearing in quiet. The replication sample included 300 healthy young adults (18-37 years) with self-reported normal hearing. Self-reported SIN deficits were assessed by the Speech, Spatial and Qualities of Hearing Scale (SSQ12). QuickSIN and Dichotic Digit Test (DDT) were performed to evaluate SIN processing. DNA samples from the saliva were subjected to low-pass whole genome sequencing. PRS calculation was performed using a custom PRS calculator. Around 2600 PRS models were derived from an open-access Polygenic Risk Score catalog. A logistic regression model was used to identify the PRS predictors associated with SIN deficits in the UK Biobank cohort. A linear mixed model was utilized to identify PRS predictors of SSQ12, QuickSIN, and DDT in the replication cohort.

Results: The regression analysis identified PRS predictors across the health spectrum associated with SIN deficits in the UK Biobank. PRS of sensory traits, such as acquired hearing loss and tinnitus, revealed significant associations with SIN deficits. PRS of neuropsychiatric conditions, including schizophrenia, major depression disorder, self-reported depression, anxiety, and risk-taking tendency, revealed robust associations with SIN deficits. Several PRS across the health spectrum, including autism spectrum disorder, alcohol consumption, body mass index, cholesterol, and lung cancer revealed significant associations with SIN deficits. PRS associated with SIN deficits were enriched (overexpressed) in several trait categories, including neuropsychiatric, mental health, and endocrine/metabolic. The replication analysis using SSQ12, QuickSIN, and DDT revealed complementary results.

Conclusion: The present study identified genetic comorbidities associated with SIN deficits in individuals with self-reported normal hearing in two independent cohorts. The results indicate that genetic predisposition to certain health traits can explain intersubject variability in SIN deficits. The results are consistent with the polygenic inheritance of SIN deficits. We posit that efficient communication of the genetic risk of SIN deficits at younger ages can help prevent or delay the onset of clinical representation of SIN deficits.