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1.
Am J Hum Genet ; 105(1): 89-107, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31204013

RESUMO

Deciphering the impact of genetic variation on gene regulation is fundamental to understanding common, complex human diseases. Although histone modifications are important markers of gene regulatory elements of the genome, any specific histone modification has not been assayed in more than a few individuals in the human liver. As a result, the effects of genetic variation on histone modification states in the liver are poorly understood. Here, we generate the most comprehensive genome-wide dataset of two epigenetic marks, H3K4me3 and H3K27ac, and annotate thousands of putative regulatory elements in the human liver. We integrate these findings with genome-wide gene expression data collected from the same human liver tissues and high-resolution promoter-focused chromatin interaction maps collected from human liver-derived HepG2 cells. We demonstrate widespread functional consequences of natural genetic variation on putative regulatory element activity and gene expression levels. Leveraging these extensive datasets, we fine-map a total of 74 GWAS loci that have been associated with at least one complex phenotype. Our results reveal a repertoire of genes and regulatory mechanisms governing complex disease development and further the basic understanding of genetic and epigenetic regulation of gene expression in the human liver tissue.

2.
Nat Commun ; 10(1): 1260, 2019 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-30890710

RESUMO

Osteoporosis is a devastating disease with an essential genetic component. GWAS have discovered genetic signals robustly associated with bone mineral density (BMD), but not the precise localization of effector genes. Here, we carry out physical and direct variant to gene mapping in human mesenchymal progenitor cell-derived osteoblasts employing a massively parallel, high resolution Capture C based method in order to simultaneously characterize the genome-wide interactions of all human promoters. By intersecting our Capture C and ATAC-seq data, we observe consistent contacts between candidate causal variants and putative target gene promoters in open chromatin for ~ 17% of the 273 BMD loci investigated. Knockdown of two novel implicated genes, ING3 at 'CPED1-WNT16' and EPDR1 at 'STARD3NL', inhibits osteoblastogenesis, while promoting adipogenesis. This approach therefore aids target discovery in osteoporosis, here on the example of two relevant genes involved in the fate determination of mesenchymal progenitors, and can be applied to other common genetic diseases.


Assuntos
Densidade Óssea/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Osteoporose/genética , Regiões Promotoras Genéticas/genética , Adipogenia/genética , Adulto , Diferenciação Celular/genética , Mapeamento Cromossômico , Feminino , Técnicas de Silenciamento de Genes , Loci Gênicos/genética , Células Hep G2 , Proteínas de Homeodomínio/genética , Humanos , Masculino , Proteínas de Membrana/genética , Células-Tronco Mesenquimais , Proteínas de Neoplasias/genética , Osteoblastos/fisiologia , Osteogênese/genética , Polimorfismo de Nucleotídeo Único , Cultura Primária de Células , Proteínas Proto-Oncogênicas/genética , RNA Interferente Pequeno/metabolismo , Proteínas Supressoras de Tumor/genética , Proteínas Wnt/genética , Adulto Jovem
3.
Diabetes Care ; 41(11): 2396-2403, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30254083

RESUMO

OBJECTIVE: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype. RESEARCH DESIGN AND METHODS: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects (n = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes (n = 2,454 vs. 968) and type 2 diabetes (n = 2,779 vs. 10,396). RESULTS: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring PFKFB3, encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes. CONCLUSIONS: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.

4.
Trends Endocrinol Metab ; 29(9): 638-650, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30041834

RESUMO

Latent autoimmune diabetes in adults (LADA) is characterized by the presence of islet autoantibodies and initial insulin independence, which can lead to misdiagnosis of type 2 diabetes (T2D). As such, understanding the genetic etiology of LADA could aid in more accurate diagnosis. However, there is ongoing debate regarding the exact definition of LADA, so understanding its impact in different populations when contrasted with type 1 diabetes (T1D) and T2D is one potential strategy to gain insight into its etiology. Unfortunately, the lack of consistent and thorough autoantibody screening around the world has hampered well-powered genetic studies of LADA. This review highlights recent genetic and epidemiological studies of LADA in diverse populations as well as the importance of autoantibody screening in facilitating future research.

5.
BMC Med ; 15(1): 88, 2017 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-28438156

RESUMO

BACKGROUND: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes. METHODS: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls. RESULTS: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted. CONCLUSION: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.


Assuntos
Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 2/genética , Adulto , Idoso , Alelos , Humanos , Pessoa de Meia-Idade , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética
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