RESUMEN
Unhealthful dietary habits are leading risk factors for life-altering diseases and mortality. Large-scale biobanks now enable genetic analysis of traits with modest heritability, such as diet. We perform a genomewide association on 85 single food intake and 85 principal component-derived dietary patterns from food frequency questionnaires in UK Biobank. We identify 814 associated loci, including olfactory receptor associations with fruit and tea intake; 136 associations are only identified using dietary patterns. Mendelian randomization suggests our top healthful dietary pattern driven by wholemeal vs. white bread consumption is causally influenced by factors correlated with education but is not strongly causal for coronary artery disease or type 2 diabetes. Overall, we demonstrate the value in complementary phenotyping approaches to complex dietary datasets, and the utility of genomic analysis to understand the relationships between diet and human health.
Asunto(s)
Bancos de Muestras Biológicas , Conducta Alimentaria , Estudios de Asociación Genética , Genómica , Ingestión de Alimentos , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Patrón de Herencia/genética , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal , Receptores Odorantes/metabolismo , Factores de Riesgo , Reino UnidoRESUMEN
BACKGROUND: The onset of puberty is first detected as an increase in pulsatile secretion of gonadotropin-releasing hormone (GnRH). Early activation of the hypothalamic-pituitary-gonadal axis results in central precocious puberty. The timing of pubertal development is driven in part by genetic factors, but only a few, rare molecular defects associated with central precocious puberty have been identified. METHODS: We performed whole-exome sequencing in 40 members of 15 families with central precocious puberty. Candidate variants were confirmed with Sanger sequencing. We also performed quantitative real-time polymerase-chain-reaction assays to determine levels of messenger RNA (mRNA) in the hypothalami of mice at different ages. RESULTS: We identified four novel heterozygous mutations in MKRN3, the gene encoding makorin RING-finger protein 3, in 5 of the 15 families; both sexes were affected. The mutations included three frameshift mutations, predicted to encode truncated proteins, and one missense mutation, predicted to disrupt protein function. MKRN3 is a paternally expressed, imprinted gene located in the Prader-Willi syndrome critical region (chromosome 15q11-q13). All affected persons inherited the mutations from their fathers, a finding that indicates perfect segregation with the mode of inheritance expected for an imprinted gene. Levels of Mkrn3 mRNA were high in the arcuate nucleus of prepubertal mice, decreased immediately before puberty, and remained low after puberty. CONCLUSIONS: Deficiency of MKRN3 causes central precocious puberty in humans. (Funded by the National Institutes of Health and others.).