RESUMEN
Lithium is the mainstay prophylactic treatment for bipolar disorder (BD), but treatment response varies considerably across individuals. Patients who respond well to lithium treatment might represent a relatively homogeneous subtype of this genetically and phenotypically diverse disorder. Here, we performed genome-wide association studies (GWAS) to identify (i) specific genetic variations influencing lithium response and (ii) genetic variants associated with risk for lithium-responsive BD. Patients with BD and controls were recruited from Sweden and the United Kingdom. GWAS were performed on 2698 patients with subjectively defined (self-reported) lithium response and 1176 patients with objectively defined (clinically documented) lithium response. We next conducted GWAS comparing lithium responders with healthy controls (1639 subjective responders and 8899 controls; 323 objective responders and 6684 controls). Meta-analyses of Swedish and UK results revealed no significant associations with lithium response within the bipolar subjects. However, when comparing lithium-responsive patients with controls, two imputed markers attained genome-wide significant associations, among which one was validated in confirmatory genotyping (rs116323614, P=2.74 × 10(-8)). It is an intronic single-nucleotide polymorphism (SNP) on chromosome 2q31.2 in the gene SEC14 and spectrin domains 1 (SESTD1), which encodes a protein involved in regulation of phospholipids. Phospholipids have been strongly implicated as lithium treatment targets. Furthermore, we estimated the proportion of variance for lithium-responsive BD explained by common variants ('SNP heritability') as 0.25 and 0.29 using two definitions of lithium response. Our results revealed a genetic variant in SESTD1 associated with risk for lithium-responsive BD, suggesting that the understanding of BD etiology could be furthered by focusing on this subtype of BD.
Asunto(s)
Trastorno Bipolar/genética , Proteínas Portadoras/genética , Adulto , Antimaníacos/uso terapéutico , Biomarcadores Farmacológicos/sangre , Trastorno Bipolar/metabolismo , Proteínas Portadoras/metabolismo , Femenino , Predisposición Genética a la Enfermedad/genética , Variación Genética , Estudio de Asociación del Genoma Completo/métodos , Genotipo , Humanos , Litio/metabolismo , Litio/uso terapéutico , Compuestos de Litio/uso terapéutico , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Autoinforme , Suecia , Reino UnidoRESUMEN
In brief Overuse injuries can be particularly challenging to manage. An athlete's premature return to athletic activity often results in recurrent and recalcitrant injury. A five-step management plan that includes establishing a pathoanatomic diagnosis, controlling inflammation, promoting healing, increasing fitness, and controlling abusive activity offers athletes optimal opportunity to return successfully to athletic performance.