Human-lineage-specific genomic elements are associated with neurodegenerative disease and APOE transcript usage
Authors: Chen Zhongbo , Zhang David , Reynolds Regina H. , Gustavsson Emil K. , García-Ruiz Sonia , D’Sa Karishma , Fairbrother-Browne Aine , Vandrovcova Jana ,   International Parkinson’s Disease Genomics Consortium (IPDGC), Noyce Alastair J. , Kaiyrzhanov Rauan , Middlehurst Ben , Kia Demis A. , Tan Manuela , Morris Huw R. , Plun-Favreau Helene , Holmans Peter , Trabzuni Daniah , Bras Jose , Quinn John , Mok Kin Y. , Kinghorn Kerri J. , Billingsley Kimberley , Wood Nicholas W. , Lewis Patrick , Schreglmann Sebastian , Guerreiro Rita , Lovering Ruth , R’Bibo Lea , Manzoni Claudia , Rizig Mie , Guelfi Sebastian , Escott-Price Valentina , Chelban Viorica , Foltynie Thomas , Williams Nigel , Brice Alexis , Danjou Fabrice , Lesage Suzanne , Corvol Jean-Christophe , Martinez Maria , Schulte Claudia , Brockmann Kathrin , Simón-Sánchez Javier , Heutink Peter , Rizzu Patrizia , Sharma Manu , Gasser Thomas , Nicolas Aude , Cookson Mark R. , Bandres-Ciga Sara , Blauwendraat Cornelis , Craig David W. , Faghri Faraz , Gibbs J. Raphael , Hernandez Dena G. , Van Keuren-Jensen Kendall , Shulman Joshua M. , Leonard Hampton L. , Nalls Mike A. , Robak Laurie , Lubbe Steven , Finkbeiner Steven , Mencacci Niccolo E. , Lungu Codrin , Singleton Andrew B. , Scholz Sonja W. , Reed Xylena , Alcalay Roy N. , Gan-Or Ziv , Rouleau Guy A. , Krohn Lynne , van Hilten Jacobus J. , Marinus Johan , Adarmes-Gómez Astrid D. , Aguilar Miquel , Alvarez Ignacio , Alvarez Victoria , Barrero Francisco Javier , Yarza Jesús Alberto Bergareche , Bernal-Bernal Inmaculada , Blazquez Marta , Bonilla-Toribio Marta , Botía Juan A. , Boungiorno María Teresa , Buiza-Rueda Dolores , Cámara Ana , Carrillo Fátima , Carrión-Claro Mario , Cerdan Debora , Clarimón Jordi , Compta Yaroslau , Diez-Fairen Monica , Dols-Icardo Oriol , Duarte Jacinto , Duran Raquel , Escamilla-Sevilla Francisco , Ezquerra Mario , Feliz Cici , Fernández Manel , Fernández-Santiago Rubén , Garcia Ciara , García-Ruiz Pedro , Gómez-Garre Pilar , Heredia Maria Jose Gomez , Gonzalez-Aramburu Isabel , Pagola Ana Gorostidi , Hoenicka Janet , Infante Jon , Jesús Silvia , Jimenez-Escrig Adriano , Kulisevsky Jaime , Labrador-Espinosa Miguel A. , Lopez-Sendon Jose Luis , de Munain Arregui Adolfo López , Macias Daniel , Torres Irene Martínez , Marín Juan , Marti Maria Jose , Martínez-Castrillo Juan Carlos , Méndez-del-Barrio Carlota , González Manuel Menéndez , Mata Marina , Mínguez Adolfo , Mir Pablo , Rezola Elisabet Mondragon , Muñoz Esteban , Pagonabarraga Javier , Pastor Pau , Errazquin Francisco Perez , Periñán-Tocino Teresa , Ruiz-Martínez Javier , Ruz Clara , Rodriguez Antonio Sanchez , Sierra María , Suarez-Sanmartin Esther , Tabernero Cesar , Tartari Juan Pablo , Tejera-Parrado Cristina , Tolosa Eduard , Valldeoriola Francesc , Vargas-González Laura , Vela Lydia , Vives Francisco , Zimprich Alexander , Pihlstrom Lasse , Toft Mathias , Koks Sulev , Taba Pille , Hassin-Baer Sharon , Hardy John , Houlden Henry , Gagliano Taliun Sarah A. , Botía Juan , Ryten Mina 
Published: April 2021

Knowledge of genomic features specific to the human lineage may provide insights into brain-related diseases. We leverage high-depth whole genome sequencing data to generate a combined annotation identifying regions simultaneously depleted for genetic variation (constrained regions) and poorly conserved across primates. We propose that these constrained, non-conserved regions (CNCRs) have been subject to human-specific purifying selection and are enriched for brain-specific elements. We find that CNCRs are depleted from protein-coding genes but enriched within lncRNAs. We demonstrate that per-SNP heritability of a range of brain-relevant phenotypes are enriched within CNCRs. We find that genes implicated in neurological diseases have high CNCR density, including APOE, highlighting an unannotated intron-3 retention event. Using human brain RNA-sequencing data, we show the intron-3-retaining transcript to be more abundant in Alzheimer’s disease with more severe tau and amyloid pathological burden. Thus, we demonstrate potential association of human-lineage-specific sequences in brain development and neurological disease.