BRIEF RESEARCH REPORT published: 10 January 2020 doi: 10.3389/fneur.2019.01362 Frontiers in Neurology | www.frontiersin.org 1 January 2020 | Volume 10 | Article 1362 Edited by: Jingyun Yang, Rush University Medical Center, United States Reviewed by: Chuntao Zhao, Cincinnati Children’s Hospital Medical Center, United States Jun Mitsui, The University of Tokyo, Japan *Correspondence: Teresa Esposito teresa.esposito@igb.cnr.it † These authors have contributed equally to this work ‡ A list of members of the IPDGC can be found in Supplementary File 1 Specialty section: This article was submitted to Neuroepidemiology, a section of the journal Frontiers in Neurology Received: 27 July 2019 Accepted: 10 December 2019 Published: 10 January 2020 Citation: Gialluisi A, Reccia MG, Tirozzi A, Nutile T, Lombardi A, De Sanctis C, International Parkinson’s Disease Genomic Consortium (IPDGC), Varanese S, Pietracupa S, Modugno N, Simeone A, Ciullo M and Esposito T (2020) Whole Exome Sequencing Study of Parkinson Disease and Related Endophenotypes in the Italian Population. Front. Neurol. 10:1362. doi: 10.3389/fneur.2019.01362 Whole Exome Sequencing Study of Parkinson Disease and Related Endophenotypes in the Italian Population Alessandro Gialluisi 1 , Mafalda Giovanna Reccia 1† , Alfonsina Tirozzi 1† , Teresa Nutile 2 , Alessia Lombardi 1 , Claudia De Sanctis 1 , International Parkinson’s Disease Genomic Consortium (IPDGC) ‡ , Sara Varanese 1 , Sara Pietracupa 1 , Nicola Modugno 1 , Antonio Simeone 2 , Marina Ciullo 1,2 and Teresa Esposito 1,2 * 1 IRCCS Neuromed, Pozzilli, Italy, 2 Institute of Genetics and Biophysics, National Research Council, Naples, Italy Parkinson Disease (PD) is a complex neurodegenerative disorder characterized by large genetic heterogeneity and missing heritability. Since the genetic background of PD can partly vary among ethnicities and neurological scales have been scarcely investigated in a PD setting, we performed an exploratory Whole Exome Sequencing (WES) analysis of 123 PD patients from mainland Italy, investigating scales assessing motor (UPDRS), cognitive (MoCA), and other non-motor symptoms (NMS). We performed variant prioritization, followed by targeted association testing of prioritized variants in 446 PD cases and 211 controls. Then we ran Exome-Wide Association Scans (EWAS) within sequenced PD cases (N = 113), testing both motor and non-motor PD endophenotypes, as well as their associations with Polygenic Risk Scores (PRS) influencing brain subcortical volumes. We identified a variant associated with PD, rs201330591 in GTF2H2 (5q13; alternative T allele: OR [CI] = 8.16[1.08; 61.52], FDR = 0.048), which was not replicated in an independent cohort of European ancestry (1,148 PD cases, 503 controls). In the EWAS, polygenic analyses revealed statistically significant multivariable associations of amygdala- [β(SE) =−0.039(0.013); FDR = 0.039] and caudate-PRS [0.043(0.013); 0.028] with motor symptoms. All subcortical PRSs in a multivariable model notably increased the variance explained in motor (adjusted-R 2 = 38.6%), cognitive (32.2%) and other non-motor symptoms (28.9%), compared to baseline models (∼20%). Although, the small sample size warrants further replications, these findings suggest shared genetic architecture between PD symptoms and subcortical structures, and provide interesting clues on PD genetic and neuroimaging features. Keywords: Parkinson disease, genetics, whole exome sequencing, cognitive performance, motor symptoms, non-motor symptoms, subcortical volumes, polygenic scores