Genome-wide structural variant analysis identifies risk loci for non-Alzheimer’s dementias

Karri Kaivola ,Letizia Mazzini,Johnathan Cooper‐Knock ,Luigi Ferrucci ,Randy Woltjer ,Francesca Brett ,Robert Bowser ,Seth Love ,Vilas Menon ,Suzanne Lesage ,Daniel Alcolea ,Pau Pástor ,Jinhui Ding ,Jeffrey D Rothstein ,James R Broach ,Ziv Gan‐Or ,Meila Tuck ,David J Stone ,Ekaterina Rogaeva ,Eva L Feldman ,Zbigniew K Wszołek ,Matthew Harms ,Ted M Dawson ,Ian Mckeith ,Xijun Zhang ,Pentti J Tienari ,Harrison Brand ,David S Goldstein ,Huw R Morris ,Jonathan D Glass ,Sultana Solaiman ,Julia Keith ,Jose‐Alberto Palma ,Miko Valori ,Ronald L Walton ,Antonio Canosa ,Ali Torkamani ,Michael Sendtner ,Matthew D Wilkerson ,Liisa Myllykangas ,Patrick May ,Hannu Laaksovirta ,Kathy L Newell ,Gauthaman Sukumar ,Tanis J Ferman ,Qinwen Mao ,William Camu ,Erik P Pioro ,Ruth Chia ,Pascual Sánchez‐Juan ,Susan M Resnick ,Anindita Ray ,Daniel Hupalo ,Dag Aarsland ,Lynn M Bekris ,Clifton L Dalgard ,Edwin S Monuki ,Jatinder Singh ,Christopher M Morris ,Juan C Troncoso ,Bryan J Traynor ,Carsten Drepper ,Dennis W Dickson ,Philip L De Jager ,M Barrett ,Johannes Attems ,Alberto Lleó ,Vivian E Drory ,Travis Dunckley ,Andrea Calvo ,Zachary Simmons ,Claire Troakes ,Camille Alba ,Michael E Talkowski ,Horacio Kaufmann ,Laura Palmer ,Thor D Stein ,Nicholas J Maragakis ,Vivianna M Van Deerlin ,Alison M Goate ,Ludo Van Den Bosch ,Tatiana Foroud ,David A Bennett ,J Raphael Gibbs ,Sandra E Black ,Masashi Fujita ,Jon Infante ,Owen A Ross ,Ryan L Collins ,Kelley Faber ,Bernardino Ghetti ,Sonja W Scholz ,Bradley F Boeve ,Laksh Malik ,Coralie Viollet ,John Hardy ,Pamela J Shaw ,Toshiko Tanaka ,Francesco Landi ,Matthew Perkins ,Alan Thomas ,Thomas G Beach ,Janine Kirby ,Xuefang Zhao ,Ellen Sidransky ,Jordi Clarimón ,Adelani Adeleye ,Ramita Dewan ,Memoona Rasheed ,Kimberley Billingsley ,Isabelle Le Ber ,Pietro Fratta ,Neill R Graff‐Radford ,Richard W Orrell ,Ali Stark ,Angela Hodges ,Clemens R Scherzer ,Safa Al‐Sarraj ,Elisa Mcgrath Martinez ,James B Leverenz ,Vikram G Shakkottai ,Lilja Jansson ,Justin Kwan ,Liana S Rosenthal ,Lyle W Ostrow ,Wim Robberecht ,Alan E Renton ,Stuart Pickering‐Brown ,Isabel González Aramburu ,Geidy E Serrano ,Roger Pamphlett ,Margaret E Flanagan ,Glenn S Gerhard ,Giancarlo Logroscino ,Olga Pletniková ,Alexis Brice ,Reijko Krüger ,Nathaniel Lott ,Steve Gentleman ,Juan Fortea ,Summer Gibson ,Pilar Alvarez Jerez ,Philip Van Damme ,Daniel Macgowan ,Sandra D’alfonso ,Katie Sidle ,Anthony R Soltis ,Carmen Lage ,John Ravits ,Walter A Kukull ,John E Landers ,Eliezer Masliah ,Terry Heiman‐Patterson ,Adriano Chiò ,Marilyn Albert ,Mario Masellis ,Nahid Tayebi ,Gabriele Mora ,Georgia Xiromerisiou ,Eric J Topol ,Serge Lumbroso ,Dagmar Bačíková ,Robert H Baloh ,Kévin Mouzat ,Grisel Lopez ,Harvey B Pollard ,Mina Ryten ,Stefan M Pulst ,Lorne Zinman

doi:10.1016/j.xgen.2023.100316

Abstract

We characterized the role of structural variants, a largely unexplored type of genetic variation, in two non-Alzheimer's dementias, namely Lewy body dementia (LBD) and frontotemporal dementia (FTD)/amyotrophic lateral sclerosis (ALS). To do this, we applied an advanced structural variant calling pipeline (GATK-SV) to short-read whole-genome sequence data from 5,213 European-ancestry cases and 4,132 controls. We discovered, replicated, and validated a deletion in TPCN1 as a novel risk locus for LBD and detected the known structural variants at the C9orf72 and MAPT loci as associated with FTD/ALS. We also identified rare pathogenic structural variants in both LBD and FTD/ALS. Finally, we assembled a catalog of structural variants that can be mined for new insights into the pathogenesis of these understudied forms of dementia.

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