Browsing by Author "Makarious, Mary B."

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    Characterizing a complex CT-rich haplotype in intron 4 of SNCA using large-scale targeted amplicon long-read sequencing
    (Springer Nature, 2024) Alvarez Jerez, Pilar; Daida, Kensuke; Grenn, Francis P.; Malik, Laksh; Miano-Burkhardt, Abigail; Makarious, Mary B.; Ding, Jinhui; Gibbs, J. Raphael; Moore, Anni; Reed, Xylena; Nalls, Mike A.; Shah, Syed; Mahmoud, Medhat; Sedlazeck, Fritz J.; Dolzhenko, Egor; Park, Morgan; Iwaki, Hirotaka; Casey, Bradford; Ryten, Mina; Blauwendraat, Cornelis; Singleton, Andrew B.; Billingsley, Kimberley J.
    Parkinson’s disease (PD) is a common neurodegenerative disorder with a significant risk proportion driven by genetics. While much progress has been made, most of the heritability remains unknown. This is in-part because previous genetic studies have focused on the contribution of single nucleotide variants. More complex forms of variation, such as structural variants and tandem repeats, are already associated with several synucleinopathies. However, because more sophisticated sequencing methods are usually required to detect these regions, little is understood regarding their contribution to PD. One example is a polymorphic CT-rich region in intron 4 of the SNCA gene. This haplotype has been suggested to be associated with risk of Lewy Body (LB) pathology in Alzheimer’s Disease and SNCA gene expression, but is yet to be investigated in PD. Here, we attempt to resolve this CT-rich haplotype and investigate its role in PD. We performed targeted PacBio HiFi sequencing of the region in 1375 PD cases and 959 controls. We replicate the previously reported associations and a novel association between two PD risk SNVs (rs356182 and rs5019538) and haplotype 4, the largest haplotype. Through quantitative trait locus analyzes we identify a significant haplotype 4 association with alternative CAGE transcriptional start site usage, not leading to significant differential SNCA gene expression in post-mortem frontal cortex brain tissue. Therefore, disease association in this locus might not be biologically driven by this CT-rich repeat region. Our data demonstrates the complexity of this SNCA region and highlights that further follow up functional studies are warranted.
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    Genome-Wide Analysis of Structural Variants in Parkinson Disease
    (Wiley, 2023) Billingsley, Kimberley J.; Ding, Jinhui; Jerez, Pilar Alvarez; Illarionova, Anastasia; Levine, Kristin; Grenn, Francis P.; Makarious, Mary B.; Moore, Anni; Vitale, Daniel; Reed, Xylena; Hernandez, Dena; Torkamani, Ali; Ryten, Mina; Hardy, John; Consortium (UKBEC), UK Brain Expression; Chia, Ruth; Scholz, Sonja W.; Traynor, Bryan J.; Dalgard, Clifton L.; Ehrlich, Debra J.; Tanaka, Toshiko; Ferrucci, Luigi; Beach, Thomas G.; Serrano, Geidy E.; Quinn, John P.; Bubb, Vivien J.; Collins, Ryan L; Zhao, Xuefang; Walker, Mark; Pierce-Hoffman, Emma; Brand, Harrison; Talkowski, Michael E.; Casey, Bradford; Cookson, Mark R; Markham, Androo; Nalls, Mike A.; Mahmoud, Medhat; Sedlazeck, Fritz J; Blauwendraat, Cornelis; Gibbs, J. Raphael; Singleton, Andrew B.
    Objective Identification of genetic risk factors for Parkinson disease (PD) has to date been primarily limited to the study of single nucleotide variants, which only represent a small fraction of the genetic variation in the human genome. Consequently, causal variants for most PD risk are not known. Here we focused on structural variants (SVs), which represent a major source of genetic variation in the human genome. We aimed to discover SVs associated with PD risk by performing the first large-scale characterization of SVs in PD. Methods We leveraged a recently developed computational pipeline to detect and genotype SVs from 7,772 Illumina short-read whole genome sequencing samples. Using this set of SV variants, we performed a genome-wide association study using 2,585 cases and 2,779 controls and identified SVs associated with PD risk. Furthermore, to validate the presence of these variants, we generated a subset of matched whole-genome long-read sequencing data. Results We genotyped and tested 3,154 common SVs, representing over 412 million nucleotides of previously uncatalogued genetic variation. Using long-read sequencing data, we validated the presence of three novel deletion SVs that are associated with risk of PD from our initial association analysis, including a 2 kb intronic deletion within the gene LRRN4. Interpretation We identified three SVs associated with genetic risk of PD. This study represents the most comprehensive assessment of the contribution of SVs to the genetic risk of PD to date. ANN NEUROL 2023;93:1012–1022
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    Profiling complex repeat expansions in RFC1 in Parkinson’s disease
    (Springer Nature, 2024) Alvarez Jerez, Pilar; Daida, Kensuke; Miano-Burkhardt, Abigail; Iwaki, Hirotaka; Malik, Laksh; Cogan, Guillaume; Makarious, Mary B.; Sullivan, Roisin; Vandrovcova, Jana; Ding, Jinhui; Gibbs, J. Raphael; Markham, Androo; Nalls, Mike A.; Kesharwani, Rupesh K.; Sedlazeck, Fritz J.; Casey, Bradford; Hardy, John; Houlden, Henry; Blauwendraat, Cornelis; Singleton, Andrew B.; Billingsley, Kimberley J.
    A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson’s disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson’s Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.