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Objective: To test the hypothesis that rs573116164 will have disease-modifying effects in patients with superoxide dismutase 1 ( SOD1 ) familial amyotrophic lateral sclerosis (fALS), we characterized rs573116164 within a cohort of 190 patients with fALS and 560 healthy age-matched controls to assess the variant for association with various measures of disease., Methods: Using a previously described bioinformatics evaluation algorithm, a polymorphic short structural variant associated with SOD1 was identified according to its theoretical effect on gene expression. An 12-18 poly-T repeat (rs573116164) within the 3' untranslated region of serine and arginine rich proteins-related carboxy terminal domain associated factor 4 ( SCAF4 ), a gene that is adjacent to SOD1 , was assessed for disease association and influence on survival and age at onset in an fALS cohort using PCR, Sanger sequencing, and capillary separation techniques for allele detection., Results: In a North American cohort of predominantly SOD1 fALS patients (n =190) and age-matched healthy controls (n = 560), we showed that carriage of an 18T SCAF4 allele was associated with disease within this cohort (odds ratio [OR] 6.6; 95% confidence interval [CI] 3.9-11.2; p = 4.0e-11), but also within non- SOD1 cases (n = 27; OR 5.3; 95% CI 1.9-14.5; p = 0.0014). This finding suggests genetically SOD1 -independent effects of SCAF4 on fALS susceptibility. Furthermore, carriage of an 18T allele was associated with a 26-month reduction in survival time (95% CI 6.6-40.8; p = 0.014), but did not affect age at onset of disease., Conclusions: The findings in this fALS cohort suggest that rs573116164 could have SOD1 -independent and broader relevance in ALS, warranting further investigation in other fALS and sporadic ALS cohorts, as well as studies of functional effects of the 18T variant on gene expression., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Total joint arthroplasty (TJA) is one of the most frequent surgical procedures performed in modern hospitals, and aseptic loosening is the most common indication for revision surgeries. We conducted a systemic exploration of potential genetic determinants for early aseptic loosening., Methods: Data from 423 patients undergoing TJA were collected and analyzed. Three analytical groups were formed based on joint arthroplasty status. Group 1 were TJA patients without symptoms of aseptic loosening of at least 1 year, group 2 were patients with primary TJA, and group 3 were patients receiving revision surgery because of aseptic loosening. Genome-wide genotyping comparing genotype frequencies between patients with and without aseptic loosening (group 3 vs groups 1 and 2) was conducted. A case-control association analysis and linear modeling were applied to identify the impact of the identified genes on implant survival with time to the revision as an outcome measure., Results: We identified 52 single-nucleotide polymorphisms (SNPs) with a genome-wide suggestive P value less than 10 -5 to be associated with the implant loosening. The most remarkable odds ratios (OR) were found with the variations in the IFIT2/IFIT3 (OR, 21.6), CERK (OR, 12.6), and PAPPA (OR, 14.0) genes. Variations in the genotypes of 4 SNPs-rs115871127, rs16823835, rs13275667, and rs2514486-predicted variability in the time to aseptic loosening. The time to aseptic loosening varied from 8 to 16 years depending on the genotype, indicating a substantial effect of genetic variance., Conclusion: Development of the aseptic loosening is associated with several genetic variations and we identified at least 4 SNPs with a significant effect on the time for loosening. These data could help to develop a personalized approach for TJA and loosening management., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson's disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial function-associated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD., Competing Interests: Competing interestsMike A. Nalls’ participation is supported by a consulting contract between Data Tecnica International and the National Institute on Aging, NIH, Bethesda, MD, USA, as a possible conflict of interest Dr. Nalls also consults for Neuro23 Inc, Lysosomal Therapeutics Inc, the Michael J. Fox Foundation, Illumina Inc. and Vivid Genomics among others. Dr. Gan-or also consults for for Lysosomal Therapeutics Inc., Denaly, Prevail Therapeutics, Idorsia, and Allergan. The other authors declare no competing interests.

To gain further insight into the genetic architecture of psoriasis, we conducted a meta-analysis of 3 genome-wide association studies (GWAS) and 2 independent data sets genotyped on the Immunochip, including 10,588 cases and 22,806 controls. We identified 15 new susceptibility loci, increasing to 36 the number associated with psoriasis in European individuals. We also identified, using conditional analyses, five independent signals within previously known loci. The newly identified loci shared with other autoimmune diseases include candidate genes with roles in regulating T-cell function (such as RUNX3, TAGAP and STAT3). Notably, they included candidate genes whose products are involved in innate host defense, including interferon-mediated antiviral responses (DDX58), macrophage activation (ZC3H12C) and nuclear factor (NF)-κB signaling (CARD14 and CARM1). These results portend a better understanding of shared and distinctive genetic determinants of immune-mediated inflammatory disorders and emphasize the importance of the skin in innate and acquired host defense.