Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
Mol Psychiatry ; 27(12): 5028-5037, 2022 12.
Artículo en Inglés | MEDLINE | ID: mdl-36151456

RESUMEN

Endophenotypes are heritable and quantifiable traits indexing genetic liability for a disorder. Here, we examined three potential endophenotypes, working memory function, response inhibition, and reaction time variability, for attention-deficit hyperactivity disorder (ADHD) measured as a dimensional latent trait in a large general population sample derived from the Adolescent Brain Cognitive DevelopmentSM Study. The genetic risk for ADHD was estimated using polygenic risk scores (PRS) whereas ADHD traits were quantified as a dimensional continuum using Bartlett factor score estimates, derived from Attention Problems items from the Child Behaviour Checklist and Effortful Control items from the Early Adolescent Temperament Questionnaire-Revised. The three candidate cognitive endophenotypes were quantified using task-based performance measures. Higher ADHD PRSs were associated with higher ADHD traits, as well as poorer working memory performance and increased reaction time variability. Lower working memory performance, poorer response inhibition, and increased reaction time variability were associated with more pronounced ADHD traits. Working memory and reaction time variability partially statistically mediated the relationship between ADHD PRS and ADHD traits, explaining 14% and 16% of the association, respectively. The mediation effect was specific to the genetic risk for ADHD and did not generalise to genetic risk for four other major psychiatric disorders. Together, these findings provide robust evidence from a large general population sample that working memory and reaction time variability can be considered endophenotypes for ADHD that mediate the relationship between ADHD PRS and ADHD traits.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Memoria a Corto Plazo , Niño , Adolescente , Humanos , Memoria a Corto Plazo/fisiología , Tiempo de Reacción , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Endofenotipos , Herencia Multifactorial , Trastornos de la Memoria
2.
Nat Med ; 29(7): 1832-1844, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37464041

RESUMEN

Depression is a common psychiatric disorder and a leading cause of disability worldwide. Here we conducted a genome-wide association study meta-analysis of six datasets, including >1.3 million individuals (371,184 with depression) and identified 243 risk loci. Overall, 64 loci were new, including genes encoding glutamate and GABA receptors, which are targets for antidepressant drugs. Intersection with functional genomics data prioritized likely causal genes and revealed new enrichment of prenatal GABAergic neurons, astrocytes and oligodendrocyte lineages. We found depression to be highly polygenic, with ~11,700 variants explaining 90% of the single-nucleotide polymorphism heritability, estimating that >95% of risk variants for other psychiatric disorders (anxiety, schizophrenia, bipolar disorder and attention deficit hyperactivity disorder) were influencing depression risk when both concordant and discordant variants were considered, and nearly all depression risk variants influenced educational attainment. Additionally, depression genetic risk was associated with impaired complex cognition domains. We dissected the genetic and clinical heterogeneity, revealing distinct polygenic architectures across subgroups of depression and demonstrating significantly increased absolute risks for recurrence and psychiatric comorbidity among cases of depression with the highest polygenic burden, with considerable sex differences. The risks were up to 5- and 32-fold higher than cases with the lowest polygenic burden and the background population, respectively. These results deepen the understanding of the biology underlying depression, its disease progression and inform precision medicine approaches to treatment.


Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , Trastorno Bipolar , Esquizofrenia , Masculino , Femenino , Humanos , Estudio de Asociación del Genoma Completo , Depresión , Trastorno Bipolar/epidemiología , Trastorno Bipolar/genética , Esquizofrenia/epidemiología , Esquizofrenia/genética , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Trastorno por Déficit de Atención con Hiperactividad/genética , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad
3.
Nat Commun ; 13(1): 634, 2022 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-35110524

RESUMEN

Back pain is a common and debilitating disorder with largely unknown underlying biology. Here we report a genome-wide association study of back pain using diagnoses assigned in clinical practice; dorsalgia (119,100 cases, 909,847 controls) and intervertebral disc disorder (IDD) (58,854 cases, 922,958 controls). We identify 41 variants at 33 loci. The most significant association (ORIDD = 0.92, P = 1.6 × 10-39; ORdorsalgia = 0.92, P = 7.2 × 10-15) is with a 3'UTR variant (rs1871452-T) in CHST3, encoding a sulfotransferase enzyme expressed in intervertebral discs. The largest effects on IDD are conferred by rare (MAF = 0.07 - 0.32%) loss-of-function (LoF) variants in SLC13A1, encoding a sodium-sulfate co-transporter (LoF burden OR = 1.44, P = 3.1 × 10-11); variants that also associate with reduced serum sulfate. Genes implicated by this study are involved in cartilage and bone biology, as well as neurological and inflammatory processes.


Asunto(s)
Degeneración del Disco Intervertebral/genética , Desplazamiento del Disco Intervertebral/genética , Disco Intervertebral/metabolismo , Cotransportador de Sodio-Sulfato/genética , Cotransportador de Sodio-Sulfato/metabolismo , Sulfatos/metabolismo , Regiones no Traducidas 3' , Huesos/metabolismo , Estudio de Asociación del Genoma Completo , Humanos , Simportadores/genética , Simportadores/metabolismo
4.
Blood Cancer J ; 11(4): 76, 2021 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-33875642

RESUMEN

Multiple myeloma (MM) is caused by the uncontrolled, clonal expansion of plasma cells. While there is epidemiological evidence for inherited susceptibility, the molecular basis remains incompletely understood. We report a genome-wide association study totalling 5,320 cases and 422,289 controls from four Nordic populations, and find a novel MM risk variant at SOHLH2 at 13q13.3 (risk allele frequency = 3.5%; odds ratio = 1.38; P = 2.2 × 10-14). This gene encodes a transcription factor involved in gametogenesis that is normally only weakly expressed in plasma cells. The association is represented by 14 variants in linkage disequilibrium. Among these, rs75712673 maps to a genomic region with open chromatin in plasma cells, and upregulates SOHLH2 in this cell type. Moreover, rs75712673 influences transcriptional activity in luciferase assays, and shows a chromatin looping interaction with the SOHLH2 promoter. Our work provides novel insight into MM susceptibility.


Asunto(s)
Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Mieloma Múltiple/genética , Anciano , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Células Germinativas/metabolismo , Mutación de Línea Germinal , Humanos , Desequilibrio de Ligamiento , Masculino , Polimorfismo de Nucleótido Simple
6.
Nat Commun ; 7: 10572, 2016 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-26838040

RESUMEN

Creatine kinase (CK) and lactate dehydrogenase (LDH) are widely used markers of tissue damage. To search for sequence variants influencing serum levels of CK and LDH, 28.3 million sequence variants identified through whole-genome sequencing of 2,636 Icelanders were imputed into 63,159 and 98,585 people with CK and LDH measurements, respectively. Here we describe 13 variants associating with serum CK and 16 with LDH levels, including four that associate with both. Among those, 15 are non-synonymous variants and 12 have a minor allele frequency below 5%. We report sequence variants in genes encoding the enzymes being measured (CKM and LDHA), as well as in genes linked to muscular (ANO5) and immune/inflammatory function (CD163/CD163L1, CSF1, CFH, HLA-DQB1, LILRB5, NINJ1 and STAB1). A number of the genes are linked to the mononuclear/phagocyte system and clearance of enzymes from the serum. This highlights the variety in the sources of normal diversity in serum levels of enzymes.


Asunto(s)
Forma MM de la Creatina-Quinasa/genética , Creatina Quinasa/sangre , L-Lactato Deshidrogenasa/sangre , Anoctaminas , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Biomarcadores/sangre , Moléculas de Adhesión Celular Neuronal/genética , Canales de Cloruro/genética , Factor H de Complemento/genética , Femenino , Frecuencia de los Genes , Variación Genética , Cadenas beta de HLA-DQ/genética , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Islandia , Isoenzimas/genética , L-Lactato Deshidrogenasa/genética , Lactato Deshidrogenasa 5 , Factor Estimulante de Colonias de Macrófagos/genética , Masculino , Glicoproteínas de Membrana , Factores de Crecimiento Nervioso/genética , Polimorfismo de Nucleótido Simple , Receptores de Superficie Celular/genética , Receptores Inmunológicos/genética , Receptores Mensajeros de Linfocitos/genética , Receptores Depuradores , Análisis de Regresión
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA