Hicks, A. A. | Search bioRxiv

bioRxiv2019

Multi-ancestry GWAS of the electrocardiographic PR interval identifies 210 loci underlying cardiac conduction

The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality1,2. We performed multi-ancestry (N=293,051) and European only (N=271,570) genome-wide association (GWAS) meta-analyses for the PR interval, discovering 210 loci of which 149 are novel. Variants at all loci nearly doubled the percentage of heritability explained, from 33.5% to 62.6%. We observed enrichment for genes involved in cardiac muscle development/contraction and the cytoskeleton highlighting key regulation processes for atrioventricular conduction. Additionally, 19 novel loci harbour genes underlying inherited monogenic heart diseases suggesting the role of these genes in cardiovascular pathology in the general population. We showed that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease risk, including distal conduction disease, AF, atrioventricular pre-excitation, non-ischemic cardiomyopathy, and coronary heart disease. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease.

genetics↗

bioRxiv2019

Kinase inhibition of G2019S-LRRK2 restores autolysosome formation and function to reduce endogenous alpha-synuclein intracellular inclusions

The Parkinsons disease (PD)-associated kinase Leucine-Rich Repeat Kinase 2 (LRRK2) is a potent modulator of autophagy and impacts on lysosome biology and function, but unclarity exists on the precise mechanics of its role and the direction of this modulation. LRRK2 is also involved in the degradation of pathological alpha-synuclein, with pathogenic mutations precipitating neuropathology in cellular and animal models of PD, and most LRRK2 familial cases manifesting with Lewy neuropathology. Defects in autophagic processing and lysosomal degradation of alpha-synuclein have been postulated to underlie its accumulation and onset of neuropathology. Thus, it is critical to reconcile these independent pieces of information to obtain a comprehensive knowledge on LRRK2-associated pathology that could also be generalized to the idiopathic disease.\n\nHere, we report a focused investigation on the role of PD-causing G2019S-LRRK2 in the autophagy-lysosome pathway in a recombinant cell line model. Initially, we evaluated the effect of LRRK2 expression on autophagy-related transcriptome. Then, we found that G2019S-LRRK2 leads to accumulation of autophagosomes with no net effect on autophagy induction. This is linked to abnormalities in lysosome morphology and proteolytic activity that are associated with a decrease in the successful formation of autolysosomes. Despite some of these features being shared by WT-LRRK2, alpha-synuclein intracellular inclusions are specifically found in G2019S-LRRK2 cells. Pharmacological kinase inhibition is capable of rescuing defects in the autophagy-lysosome pathway and reducing the number of inclusions. Notably, this effect is prevented by upstream blockade of autophagosome-lysosome fusion events, highlighting this step of the process as critical for alpha-synuclein clearance.

cell biology↗