LATE-NC risk alleles (in TMEM106B, GRN, and ABCC9 genes) among persons with African ancestry
Authors: Katsumata Yuriko , Fardo David W , Shade Lincoln M P ,   Alzheimer’s Disease Genetics Consortium, Bowen James D , Crane Paul K , Jarvik Gail P , Keene C Dirk , Larson Eric B , McCormick Wayne C , McCurry Susan M , Mukherjee Shubhabrata , Kowall Neil W , McKee Ann C , Honig Robert A , Lawrence S , Vonsattel Jean Paul , Williamson Jennifer , Small Scott , Burke James R , Hulette Christine M , Welsh-Bohmer Kathleen A , Gearing Marla , Lah James J , Levey Allan I , Wingo Thomas S , Apostolova Liana G , Farlow Martin R , Ghetti Bernardino , Saykin Andrew J , Spina Salvatore , Albert Marilyn S , Lyketsos Constantine G , Troncoso Juan C , Frosch Matthew P , Green Robert C , Growdon John H , Hyman Bradley T , Tanzi Rudolph E , Potter Huntington , Dickson Dennis W , Ertekin-Taner Nilufer , Graff-Radford Neill R , Parisi Joseph E , Petersen Ronald C , Duara Ranjan , Buxbaum Joseph D , Goate Alison M , Sano Mary , Masurkar Arjun V , Wisniewski Thomas , Bigio Eileen H , Mesulam Marsel , Weintraub Sandra , Vassar Robert , Kaye Jeffrey A , Quinn Joseph F , Woltjer Randall L , Barnes Lisa L , Bennett David A , Schneider Julie A , Yu Lei , Henderson Victor , Fallon Kenneth B , Harrell Lindy E , Marson Daniel C , Roberson Erik D , DeCarli Charles , Jin Lee-Way , Olichney John M , Kim Ronald , LaFerla Frank M , Monuki Edwin , Head Elizabeth , Sultzer David , Geschwind Daniel H , Vinters Harry V , Chesselet Marie-Francoise , Galasko Douglas R , Brewer James B , Boxer Adam , Karydas Anna , Kramer Joel H , Miller Bruce L , Rosen Howard J , Seeley William W , Burns Jeffrey M , Swerdlow Russell H , Abner Erin , Fardo David W , Van Eldik Linda J , Albin Roger L , Lieberman Andrew P , Paulson Henry L , Arnold Steven E , Trojanowski John Q , Van Deerlin Vivianna M , Hamilton Ronald L , Kamboh M Ilyas , Lopez Oscar L , Becker James T , Cao Chuanhai , Raj Ashok , Smith Amanda G , Chui Helena C , Miller Carol A , Ringman John M , Schneider Lon S , Bird Thomas D , Sonnen Joshua A , Yu Chang-En , Grabowski Thomas , Peskind Elaine , Raskind Murray , Li Ge , Tsuang Debby W , Asthana Sanjay , Atwood Craig S , Carlsson Cynthia M , Sager Mark A , Chin Nathaniel A , Craft Suzanne , Cairns Nigel J , Morris John C , Cruchaga Carlos , Strittmatter Stephen , Reiman Eric M , Beach Thomas G , Huentelman Matthew J , Hardy John , Myers Amanda J , Kauwe John S K , Hakonarson Hakon , Blacker Deborah , Montine Thomas J , Baldwin Clinton T , Farrer Lindsay A , Jun Gyungah , Lunetta Kathryn L , Bush William S , Haines Jonathan L , Lerner Alan J , Zhou Xiongwei , Barral Sandra , Reitz Christiane , Vardarajan Badri N , Mayeux Richard , Beecham Gary W , Carney Regina M , Cuccaro Michael L , Gilbert John R , Hamilton-Nelson Kara L , Kunkle Brian W , Martin Eden R , Pericak-Vance Margaret A , Vance Jeffery M , Cantwell Laura B , Kuzma Amanda P , Malamon John , Naj Adam C , Qu Liming , Schellenberg Gerard D , Valladares Otto , Wang Li-San , Zhao Yi , Leverenz James B , De Jager Philip L , Evans Denis A , Katz Mindy J , Lipton Richard B , Boeve Bradley F , Allen Mariet , Carrasquillo Minerva M , Younkin Steven G , Kukull Walter A , Faber Kelley M , Foroud Tatiana M , Pavlik Valory , Massman Paul , Darby Eveleen , Rodriguear Monica , Khaleeq Aisha , Royall Donald R , Stevens Alan , Ory Marcia , DeToledo John C , Wilms Henrick , Johnson Kim , Perez Victoria , Hernandez Michelle , Wilhelmsen Kirk C , Tilson Jeffrey , Chasse Scott , Barber Robert C , Fairchild Thomas J , O’Bryant Sid E , Knebl Janice , Hall James R , Johnson Leigh , Mains Douglas , Alvarez Lisa , Gamboa Adriana , Paydarfar David , Bertelson John , Woon Martin , Ayres Gayle , Aguirre Alyssa , Palmer Raymond , Polk Marsha , Adams Perrie M , Huebinger Ryan M , Reisch Joan S , Rosenberg Roger N , Cullum Munro , Williams Benjamin , Quiceno Mary , Hynan Linda , Smith Janet , Davis Barb , Nguyen Trung , Rogaeva Ekaterina , George-Hyslop Peter St , Nelson Peter T 
Published: August 2023

Abstract
Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes—TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer’s Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer’s Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.