Identification of genetic risk factors in the Chinese population implicates a role of immune system in Alzheimer’s disease pathogenesis
Authors: Zhou Xiaopu , Chen Yu , Mok Kin Y. , Zhao Qianhua , Chen Keliang , Chen Yuewen , Hardy John , Li Yun , Fu Amy K. Y. , Guo Qihao , Ip Nancy Y. ,   for the Alzheimer’s Disease Neuroimaging Initiative, Saykin Andrew J. , Toga Arthur W. , Borowski Bret , Ward Chad , DeCarli Charles , Mathis Chet , Jack Clifford R. , Harvey Danielle , Holtzman David , Jones David , Gessert Devon , Lilly Eli , Reiman Eric M. , Franklin Erin , Hefti Franz , Sorensen Greg , Jimenez Gustavo , Fillit Howard , Gunter Jeff , Salazar Jennifer , Hsiao John , Morris John , Trojanowki John Q. , Neu Karen Crawford Scott , Kantarci Kejal , Faber Kelley , Harless Kelly , Chen Kewei , Nho Kwangsik , Beckett Laurel , Thal Lean , Thal Leon , Shaw Leslie M. , Kuller Lew , Shen Li , Hergesheimer Lindsey , Taylor-Reinwald Lisa , Mesulam M. Marcel , Korecka Magdalena , Raichle Marc , Carrillo Maria , Albert Marilyn , Senjem Matt , Bernstein Matthew , Donohue Michael , Weiner Michael , Figurski Michal , Buckholtz Neil , Fox Nick , Cairns Nigel J. , Schuff Norbert , Foster Norm , Aisen Paul , Thompson Paul , Davies Peter , Snyder Peter J. , Snyder Peter , Vemuri Prashanthi , Frank Richard , Koeppe Robert A. , Green Robert C. , Petersen Ronald , Walter Sarah , Paul Steven , Potkin Steven , Kim Sungeun , Foroud Tatiana M. , Montine Tom , Lee Virginia , Jagust William , Potter William , Cabrera Yuliana , Khachaturian Zaven , Fleisher Adam , Pierce Aimee , Mintz Akiva , Lerner Alan , Norbash Alexander , Levey Allan I. , Rosen Allyson , Smith Amanda , Ulysse Anaztasia , Budson Andrew E. , Kertesz Andrew , Oliver Angela , Hake Ann Marie , Burke Anna , Sarrael Antero , Porsteinsson Anton P. , Lamb Ashley , Lee Athena , Raj Balebail Ashok , Lane Barton , Yanez Beatriz , Ances Beau , Mudge Benita , Lind Betty , Stefanovic Bojana , Goldstein Bonnie S. , Bonakdarpour Borna , Matthews Brandy R. , Ott Brian R. , Reynolds Brigid , Miller Bruce L. , Spann Bryan M. , Sadowsky Carl , Bernick Charles , Smith Charles D. , Onyike Chiadi , Heyn Chris (Chinthaka) , Hosein Chris , Leach Christi , Belden Christine M. , van Dyck Christopher H. , Clark Christopher M. , Wu Chuang-Kuo , Albers Colleen S. , Brand Connie , Bodge Courtney , Tatsuoka Curtis , Carlsson Cynthia M. , Mathews Dana , D’Agostino Daniel , Silverman Daniel H.S. , Marson Daniel , Wolk David A. , Bachman David , Clark David , Geldmacher David , Hart David , Knopman David , Perry David , Winkfield David , Miller Delwyn D. , Kerwin Diana , Drost Dick , Simpson Donna M. , Munic Donna , Scharre Douglas W. , Bartha Rob , Celmins Dzintra , Zimmerman Earl A. , Teng Edmond , Coleman Edward , Zamrini Edward , Mitsis Effie , Finger Elizabeth , Oates Elizabeth , Sosa Elizabeth , Woo Ellen , Rogalski Emily , Fletcher Evan , Parfitt Francine , Thai Gaby , Marshall Gad A. , Conrad Gary , Tremont Geoffrey , Bartzokis George , Hsiung Ging-Yuek Robin , Chiang Gloria , Pearlson Godfrey D. , Jicha Greg , Vanderswag Helen , Grossman Hillel , Capote Horacio , Bergman Howard , Chertkow Howard , Feldman Howard , Rosen Howard J. , Koleva Hristina , Shim Hyungsub , Rachinsky Irina , Mintzer Jacobo , Ziolkowski Jaimie , Brewer James , Lah James J. , Singleton-Garvin Jamika , Cellar Janet S. , Brosch Jared R. , Tinklenberg Jared , Karlawish Jason H. , Villanueva-Meyer Javier , Kaye Jeffrey A. , Burns Jeffrey M. , Petrella Jeffrey R. , Yesavage Jerome , Allard Joanne , Lord Joanne L. , Hetelle Joel , Brockington John , Morris John C. , Olichney John , Rogers John , Quinn Joseph , Kass Joseph S. , Taylor Joy L. , Heidebrink Judith L. , Anderson Karen , Blank Karen , Smith Karen Ekstam , Bell Karen L. , Johnson Kathleen , Tingus Kathleen , DeMarco Kathryn , Sink Kaycee M. , Johnson Keith A. , Makino Kelly M. , Spicer Kenneth , Nam Ki Won , Martin Kim , Poki-Walker Kim , Johnson Kris , Fargher Kristin , Lipowski Kristine , Womack Kyle , Flashman Laura A. , Honig Lawrence S. , Apostolova Liana , Teodoro Liberty , Silbert Lisa C. , Ravdin Lisa , Schneider Lon S. , Daiello Lori A. , Ismail M. Saleem , Seltzer Marc , Mesulam Marek-Marsel , Carroll Maria , Kataki Maria , Greig-Custo Maria T. , Love Marissa Natelson , Mintun Mark A. , Farlow Martin R. , Sadowski Martin , Creech Mary L. , Hynes Mary L. , Quiceno Mary , Oakley MaryAnn , Becerra Mauricio , Witbracht Megan , Keltz Melanie , Lamar Melissa , Yang Mia , Borrie Michael , Lin Michael , Assaly Michele , Rainka Michelle , Dang Mimi , Sheikh Mohammed O. , Gaikwad Mrunalini , Chowdhury Munir , Trncic Nadira , Johnson Nancy , Kowalksi Nancy , Pacini Nathaniel , Kowall Neil , Graff-Radford Neill R , Relkin Norman , Oyonumo Ntekim E. , Pomara Nunzio , James Olga , Ogunlana Olu , Lopez Oscar L. , Carmichael Owen , Doraiswamy P. Murali , Fatica Parianne , Johnson Patricia Lynn , Samuels Patricia , Malloy Paul , Ogrocki Paula , Maillard Pauline , Hardy Peter , Tariot Pierre , Lu Po H. , Varma Pradeep , Doody Rachelle S. , Carter Raina , Shah Raj C. , Griffith Randall , Yeh Randy , Duara Ranjan , Tarawneh Rawan , Turner Raymond Scott , Hernando Raymundo , Sperling Reisa A. , Carson Richard E. , El Khouli Riham , Santulli Robert B. , Killiany Ronald , Rodriguez Rosemarie , Swerdlow Russell H. , Borges-Neto Salvador , Black Sandra , Weintraub Sandra , Asthana Sanjay , Vaishnavi Sanjeev , Dolen Sara , Mason Sara S. , Kremen Sarah , Herring Scott , Sirrel Sherye A. , Kittur Smita , Pawluczyk Sonia , Schneider Stacy , Kielb Stephanie , Reeder Stephanie , Correia Stephen , Pasternack Stephen , Pasternak Stephen , Salloway Stephen , Johnson Sterling , Chao Steven , Arnold Steven E. , Schultz Susan K. , Rountree Susan , Lee T-Y , Wong Terence Z. , Villena Teresa , Obisesan Thomas O. , Pavlik Valory , Bates Vernice , Sossi Vesna , Shibley Victoria , Brooks William M. , Pavlosky William , Stern Yaakov , Simon Adam , Dongre Ashok , Dean Bob , Navia Brad , Spellman Dan , Lee David , Shera David , Siemers Eric , Pickering Eve , Swenson Frank , Immerman Fred , Nomikos George , Soares Holly , Wan Hong , Seeburger Jeff , Waring Jeff , Trojanowski John , Siuciak Judy , Duffin Kevin , Shaw Les , Wang Li-San , Thambisetty Madhav , Walton Marc , Savage Mary , Ferm Mats , Kuhn Max , Buckholtz Neil , Zagouras Panos , Cole Patricia , Hendrickson Ron , Xie Sharon , Allauzen Sophie , Koroshetz Walter , Potter William 
Published: February 2018

Alzheimer’s disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the
APOE
locus (sentinel variant rs73052335,
P
= 1.44 × 10
−14
), two common variants,
GCH1
(rs72713460,
P
= 4.36 × 10
−5
) and
KCNJ15
(rs928771,
P
= 3.60 × 10
−6
), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype–phenotype analysis showed that
KCNJ15
variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the
KCNJ15
transcript can be observed in the blood of AD subjects. Moreover, the risk variants of
GCH1
and
KCNJ15
are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the
APOE
,
GCH1
, and
KCNJ15
loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of
GCH1
and
KCNJ15
in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.