Human molecular genetics
-
Human molecular genetics · May 2020
A genome-wide association study finds genetic variants associated with neck or shoulder pain in UK Biobank.
Common types of musculoskeletal conditions include pain in the neck and shoulder areas. This study seeks to identify the genetic variants associated with neck or shoulder pain based on a genome-wide association approach using 203 309 subjects from the UK Biobank cohort and look for replication evidence from the Generation Scotland: Scottish Family Health Study (GS:SFHS) and TwinsUK. ⋯ We have identified three loci associated with neck or shoulder pain in the UK Biobank cohort, two of which were weakly supported in a replication cohort. Further evidence is needed to confirm their roles in neck or shoulder pain.
-
Human molecular genetics · Jul 2019
Exploring the cross-phenotype network region of disease modules reveals concordant and discordant pathways between chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis.
Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are two pathologically distinct chronic lung diseases that are associated with cigarette smoking. Genetic studies have identified shared loci for COPD and IPF, including several loci with opposite directions of effect. The existence of additional shared genetic loci, as well as potential shared pathobiological mechanisms between the two diseases at the molecular level, remains to be explored. ⋯ Applying NetPathScore to the COPD and IPF disease modules enabled the determination of concordant and discordant pathways between these diseases. Concordant pathways between COPD and IPF included extracellular matrix remodeling, Mitogen-activated protein kinase (MAPK) signaling and ALK pathways, whereas discordant pathways included advanced glycosylation end product receptor signaling and telomere maintenance and extension pathways. Overall, our findings reveal shared molecular interaction regions between COPD and IPF and shed light on the congruent and incongruent biological processes lying at the intersection of these two complex diseases.
-
Human molecular genetics · Apr 2019
Evidence that ITGB3 promoter variants increase serotonin blood levels by regulating platelet serotonin transporter trafficking.
Elevated serotonin (5-HT) blood levels, the first biomarker identified in autism research, has been consistently found in 20-30% of patients with Autism Spectrum Disorder (ASD). Hyperserotonemia is mainly due to greater 5-HT uptake into platelets, mediated by the 5-HT transporter (SERT) located at the platelet plasma membrane. The protein complex involved in platelet SERT trafficking and externalization includes integrin β3, the beta subunit of the platelet membrane adhesive GP IIb/IIIa. ⋯ Luciferase assays in two hematopoietic cell lines, K-562 and HEL 92.1.7, demonstrate that ITGB3 gene promoter activity is enhanced by the presence of the C allele at rs55827077 specifically during differentiation into megakaryocytes (P < 0.01), with modulatory effects by flanking SNPs. This same allele is strongly associated with (a) higher 5-HT blood levels in 176 autistic individuals (P < 0.001), (b) greater platelet integrin β3 protein expression (P < 0.05) and (c) enhanced SERT trafficking from the cytosol toward the platelet plasma membrane (P = 4.05 × 10-11). Our results support rs55827077 as the functional ITGB3 gene promoter variant contributing to elevated 5-HT blood levels in ASD and define a mechanistic chain of events linking ITGB3 to hyperserotonemia.
-
Human molecular genetics · Feb 2019
Ubiquitin specific protease-13 independently regulates parkin ubiquitination and alpha-synuclein clearance in alpha-synucleinopathies.
Ubiquitin specific proteases (USPs) are de-ubiquitinases (DUBs) that control protein ubiquitination cycle. The role of DUBs is poorly understood in neurodegenerative diseases. We found that USP13 is overexpressed in post-mortem Parkinson's disease (PD) brains. ⋯ USP13 shRNA knockdown increases alpha-synuclein ubiquitination and clearance, in a parkin-independent manner. Furthermore, USP13 overexpression counteracts the effects of a tyrosine kinase inhibitor, Nilotinib, while USP13 knockdown facilitates Nilotinib effects on alpha-synculein clearance, suggesting that alpha-synuclein ubiquitnation is important for its clearance. These studies provide novel evidence of USP13 effects on parkin and alpha-synuclein metabolism and suggest that USP13 is a potential therapeutic target in the alpha-synucleinopathies.
-
Human molecular genetics · Aug 2018
ReviewDevelopment and application of CRISPR/Cas9 technologies in genomic editing.
Genomic editing to correct disease-causing mutations is a promising approach for the treatment of human diseases. As a simple and programmable nuclease-based genomic editing tool, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has substantially improved the ability to make precise changes in the human genome. ⋯ Here, we review the application of the CRISPR system over the last 2 years; including its development and application in base editing, transcription modulation and epigenetic editing, genomic-scale screening, and cell and embryo therapy. Finally, the prospects and challenges related to application of CRISPR/Cas9 technologies are discussed.