A genome-wide association study of a rage-related misophonia symptom and the genetic link with audiological traits, psychiatric disorders, and personality

Abstract

Introduction: People with misophonia experience strong negative emotional responses to sounds and associated stimuli-mostly human produced-to an extent that it may cause impairment in social functioning. The exact nature of the disorder remains a matter of ongoing research and debate. Here, we investigated the genetic etiology of misophonia to understand contributing genetic factors and shed light on individual differences in characteristics that are related to the disorder.

Methods: For misophonia, we used an unpublished genome-wide association study (GWAS) from genetic service provider 23andMe, Inc., on a self-report item probing a single common misophonic symptom: the occurrence of rage when others produce eating sounds. First, we used gene-based and functional annotation analyses to explore neurobiological determinants of the rage-related misophonia symptom. Next, we calculated genetic correlations (r _G) of this rage-related misophonia symptom GWAS with a wide range of traits and disorders from audiology (tinnitus, hearing performance, and hearing trauma), psychiatry, neurology, and personality traits.

Results: The rage-related misophonia symptom was significantly correlated with tinnitus, major depression disorder (MDD), post-traumatic stress disorder (PTSD), and generalized anxiety disorder (GAD; 0.12 < r _G < 0.22). Stronger genetic correlations (0.21 < r _G < 0.42) were observed for two clusters of personality traits: a guilt/neuroticism and an irritability/sensitivity cluster. Our results showed no genetic correlation with attention deficit and hyperactivity disorder, obsessive-compulsive disorder, and psychotic disorders. A negative correlation with autism spectrum disorder (ASD) was found, which may be surprising given the previously reported comorbidities and the sensory sensitivity reported in ASD. Clustering algorithms showed that rage-related misophonia consistently clustered with MDD, generalized anxiety, PTSD, and related personality traits.

Discussion: We conclude that-based on the genetics of a common misophonia symptom-misophonia most strongly clusters with psychiatric disorders and a personality profile consistent with anxiety and PTSD.

Keywords: audiology; genetic correlation; hatred for chewing sounds; psychiatric genomics; psychiatric nosology; psychiatry.

FIGURE 1

Genetic correlations of misophonia symptoms with a range of behavioral traits and disorders. False discovery rate (FDR)-corrected significant effects (red) were observed in most categories (audiological, psychiatric, personality, and miscellaneous traits). Nominal significance (green triangles) was observed for Anxiety, autism spectrum disorder (ASD), and “Tinnitus in good hearing”. FDR adjusted significant correlations were observed for Current Tinnitus, Ever Tinnitus, post-traumatic stress disorder (PTSD), major depression disorder (MDD), a range of internalizing and externalizing traits, and educational attainment (red).

FIGURE 2

Correlation plot between misophonia and audiological traits. SNP-based genetic correlations were calculated between misophonia and 10 audiology traits using LD-score regression (LDSC). *p < 0.05, **p < 0.01, ***p < 0.001, false discovery rate (FDR) adjusted across all traits combinations. See Supplementary Table 1 for abbreviations.

FIGURE 3

Correlation plot between misophonia, psychiatric, and psychological traits. SNP-based genetic correlations were calculated between misophonia, tinnitus (current), and 12 selected traits shows the membership of two main clusters identified using hierarchical clustering, putatively called the irritability and neuroticism clusters. The neuroticism cluster holds most internalizing traits. The irritability cluster also holds sensitivity, tenseness, and worry. The psychiatric traits are clustered with the neuroticism cluster but all showed significant positive correlations with the irritability cluster. Misophonia closely followed the psychiatric traits. Tinnitus showed a pattern different from misophonia with high correlations with the neuroticism cluster but no significant correlations with the irritability cluster. *p < 0.05, **p < 0.01, ***p < 0.001, false discovery rate (FDR) adjusted across all traits combinations. See Supplementary Table 1 for abbreviations.

FIGURE 4

Graph of the full genetic correlation matrix. Vertex colors are based on Louvain clustering algorithm. Per vertex, only the top 10 edges are shown that are over 0.10. Node size is based on the Eigen centrality of the trait calculated from the weighted correlation matrix (absolute values). Misophonia clustered with the Depressive disorders cluster [major depression disorder (MDD), post-traumatic stress disorder (PTSD), and Anxiety] which also holds related personality traits (including neuroticism, guilt, miserableness, loneliness) (blue). Irritability and related traits (worry, sensitivity, tense) cluster with hearing problems (without or with background noise), insomnia, friendship satisfaction, and Townsend index (red). Tinnitus traits clustered with “hearing aid user” (green). The remaining cluster (yellow) holds a variety of traits, which includes neuropsychiatric disorders attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), neurological disorders, substance use disorders, psychotic disorders (schizophrenia, SCZ; bipolar disorder, BIP), obsessive-compulsive-related disorders (OCD; Tourette’s Syndrome, TS; AN), and the insula measures.