Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions

Contribution of Chronic Myeloid Leukaemia (CML) as a Disease Model to Define and Study Clonal Heterogeneity

International audienc

Preclinical models of levodopa-induced dyskinesia

L -DOPA-induced dyskinesia (LID) represents one of the major limitations in the current pharmacotherapy of Parkinson's disease (PD) and affects the majority of PD patients. Animal models are the most important preclinical tool for molecular investigations of LID mechanisms and therapeutic targets. Over the last two decades, models of LID have been developed in both nonhuman primate and rodent species, recapitulating several aspects of the human dyskinesia. This chapter will review and compare the main features of the rodent and nonprimate models of LID currently available and summarize some of the main neurobiological fi ndings obtained from these models

Progressive Supranuclear Palsy and Corticobasal Degeneration.

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are neurodegenerative tauopathies with neuronal and glial lesions composed of tau that is composed predominantly of isomers with four repeats in the microtubule-binding domain (4R tau). The brain regions vulnerable to pathology in PSP and CBD overlap, but there are differences, particularly with respect to distribution of neuronal loss, the relative abundance of neuronal and glial lesions, the morphologic features of glial lesions, and the frequency of comorbid pathology. Both PSP and CBD have a wide spectrum of clinical manifestations, including disorders of movement and cognition. Recognition of phenotypic diversity in PSP and CBD may improve antemortem diagnostic accuracy, which tends to be very good for the most common presentation of PSP (Richardson syndrome), but poor for the most characteristic presentation of CBD (corticobasal syndrome: CBS). Development of molecular and imaging biomarkers may improve antemortem diagnostic accuracy. Currently, multidisciplinary symptomatic and supportive treatment with pharmacological and non-pharmacological strategies remains the standard of care. In the future, experimental therapeutic trials will be important to slow disease progression