MULTITRAIT ANALYSIS EXPANDS GENETIC RISK FACTORS IN CARDIOEMBOLIC STROKE

Background and Purpose: The genetic architecture of cardioembolic stroke (CES) is still poorly understood. Atrial fibrillation (AF) is the main cause of CES, with which it shares heritability. We aimed to discover novel loci associated with CES by performing a Multitrait Analysis of the GWAS (MTAG) with atrial fibrillation genetic data. Methods: For the MTAG analysis we used the MEGASTROKE cohort, which comprises European patients with CES and controls (n=362,661) and an AF cohort composed of 1,030,836 subjects. Regional genetic pleiotropy of the significant results was explored using an alternative Bayesian approach with GWAS-pairwise method. A replication was performed in an independent European cohort comprising 9,105 subjects using a Genome Wide Association Study (GWAS). Results: MTAG-CES analysis revealed 40 novel and significant loci (p-value<5x10-8) associated with CES, four of which had not previously been associated with AF. A significant replication was assessed for eight novel loci: CAV1, IGF1R, KIAA1755, NEURL1, PRRX1, SYNE2, TEX41 and WIPF1, showing a p-value<0.05 in the CES vs controls independent analysis. KIAA1755, a locus not previously described associated with AF. Interestingly, 51 AF risk loci were not associated with CES according to GWAS-pairwise analysis. Gene Ontology (GO) analysis revealed that these exclusive AF genes from the 51 loci participate in processes related mainly to cardiac development, whereas genes associated with AF and CES participate mainly in muscle contraction and the conduction of electrical impulses. Conclusions: We found eight new loci associated with CES. In addition, this study provides novel insights into the pathogenesis of CES, highlighting multiple candidate genes for future functional experiments.

Personality in Children With Vocal Fold Nodules: A Multitrait Analysis

Purpose Vocal fold nodules (VNs) are bilateral, symmetrical, callous-like lesions secondary to phonotrauma and possibly related to specific personality traits. This case–control study examined the relation between personality and VNs in children within the context of the Trait Theory of VNs. Method Parents of children with VNs ( N = 39, M = 7.43, SD = 2.01 years) and two medical control groups (i.e., voice disordered controls, but not VNs [VDCs; N = 40, M = 7.09, SD = 2.01 years] and vocally normal controls [VNCs; N = 40, M = 7.6, SD = 1.54 years]) completed the Inventory of Child Individual Differences, a personality instrument that describes the Big Five superfactors as well as 15 lower order personality traits. Results Children with VNs, as compared with VNCs, were (a) emotionally reactive (i.e., higher N—Neuroticism, p < .005, Cohen's d = 0.53), (b) Antagonistic, Strong-Willed, and less Compliant (i.e., lower A—Agreeableness, p < .014, Cohen's d = 0.59), and (c) Distractible and Disorganized (i.e., lower C—Conscientiousness, p < .009, Cohen's d = 0.62). Both voice disordered groups displayed elevated scores on the personality superfactor of Neuroticism (N; and the “Negative Emotions” lower order trait). Conclusions The combination of personality traits identified in this study (i.e., high N, low A and C) may play a central role in VNs development and possibly attenuate voice therapy success. Children with VNs displayed a similar personality typology as women with VNs, with the exception of elevated Extraversion (E), thereby providing support for the relevance of the Trait Theory of VNs in both children and adults. Clinicians treating children with voice disorders, including VNs, should consider their underlying personality traits in assessment and management.