RESUMEN
Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.
Asunto(s)
Alelos , Sitios Genéticos/genética , Menarquia/genética , Padres , Adolescente , Factores de Edad , Índice de Masa Corporal , Neoplasias de la Mama/genética , Proteínas de Unión al Calcio , Enfermedades Cardiovasculares/genética , Niño , Diabetes Mellitus Tipo 2/genética , Europa (Continente)/etnología , Femenino , Estudio de Asociación del Genoma Completo , Impresión Genómica/genética , Humanos , Sistema Hipotálamo-Hipofisario/fisiología , Péptidos y Proteínas de Señalización Intercelular/genética , Masculino , Proteínas de la Membrana/genética , Obesidad/genética , Ovario/fisiología , Polimorfismo de Nucleótido Simple/genética , Canales de Potasio de Dominio Poro en Tándem/genética , Proteínas/genética , Sitios de Carácter Cuantitativo/genética , Receptores de GABA-B/metabolismo , Receptores de Ácido Retinoico/metabolismo , Ribonucleoproteínas/genética , Ubiquitina-Proteína LigasasRESUMEN
The phenotypic effect of some single nucleotide polymorphisms (SNPs) depends on their parental origin. We present a novel approach to detect parent-of-origin effects (POEs) in genome-wide genotype data of unrelated individuals. The method exploits increased phenotypic variance in the heterozygous genotype group relative to the homozygous groups. We applied the method to >56,000 unrelated individuals to search for POEs influencing body mass index (BMI). Six lead SNPs were carried forward for replication in five family-based studies (of â¼4,000 trios). Two SNPs replicated: the paternal rs2471083-C allele (located near the imprinted KCNK9 gene) and the paternal rs3091869-T allele (located near the SLC2A10 gene) increased BMI equally (betaâ=â0.11 (SD), P<0.0027) compared to the respective maternal alleles. Real-time PCR experiments of lymphoblastoid cell lines from the CEPH families showed that expression of both genes was dependent on parental origin of the SNPs alleles (P<0.01). Our scheme opens new opportunities to exploit GWAS data of unrelated individuals to identify POEs and demonstrates that they play an important role in adult obesity.
Asunto(s)
Proteínas Facilitadoras del Transporte de la Glucosa/genética , Obesidad/genética , Polimorfismo de Nucleótido Simple/genética , Canales de Potasio de Dominio Poro en Tándem/genética , Adulto , Índice de Masa Corporal , Femenino , Regulación de la Expresión Génica , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Impresión Genómica , Genotipo , Humanos , Masculino , Obesidad/patología , Población Blanca/genéticaRESUMEN
Although antidepressants are widely used in the pharmacotherapy of major depressive disorder (MDD), their efficacy is still insufficient as approximately one-third of the patients do not fully recover even after several treatment trials. Inter-individual genetic differences are thought to contribute to the variability in antidepressant response; however, current findings from pharmacogenetic studies are uncertain or not clearly replicated. Here we report the first application of full exome sequencing for the analysis of pharmacogenomics on antidepressant treatment. After 12 weeks of treatment with the selective serotonin re-uptake inhibitor escitalopram, we selected five clear responders and five clear non-responders for exome sequencing. By comparing the allele counts of previously known single nucleotide polymorphisms and novel polymorphisms we selected 38 markers for further genotyping in two independent patient samples treated with escitalopram (n=116 and n=394). The A allele, carried by approximately 30% of the patients with MDD, of rs41271330 in the bone morphogenetic protein (BMP5) gene showed strong association with worse treatment response in both sample sets (p=0.001), indicating that this is an promising pharmacogenetic marker for prediction of antidepressant therapeutic outcome.