Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
23471985
TITLE
Genome-wide scan of healthy human connectome discovers SPON1 gene variant influencing dementia severity.
ABSTRACT
Aberrant connectivity is implicated in many neurological and psychiatric disorders, including Alzheimer's disease and schizophrenia. However, other than a few disease-associated candidate genes, we know little about the degree to which genetics play a role in the brain networks; we know even less about specific genes that influence brain connections. Twin and family-based studies can generate estimates of overall genetic influences on a trait, but genome-wide association scans (GWASs) can screen the genome for specific variants influencing the brain or risk for disease. To identify the heritability of various brain connections, we scanned healthy young adult twins with high-field, high-angular resolution diffusion MRI. We adapted GWASs to screen the brain's connectivity pattern, allowing us to discover genetic variants that affect the human brain's wiring. The association of connectivity with the SPON1 variant at rs2618516 on chromosome 11 (11p15.2) reached connectome-wide, genome-wide significance after stringent statistical corrections were enforced, and it was replicated in an independent subsample. rs2618516 was shown to affect brain structure in an elderly population with varying degrees of dementia. Older people who carried the connectivity variant had significantly milder clinical dementia scores and lower risk of Alzheimer's disease. As a posthoc analysis, we conducted GWASs on several organizational and topological network measures derived from the matrices to discover variants in and around genes associated with autism (MACROD2), development (NEDD4), and mental retardation (UBE2A) significantly associated with connectivity. Connectome-wide, genome-wide screening offers substantial promise to discover genes affecting brain connectivity and risk for brain diseases.
DATE PUBLISHED
2013 Mar 19
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2013/03/05
entrez 2013/03/09 06:00
pubmed 2013/03/09 06:00
medline 2013/05/25 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Jahanshad N Jahanshad Neda N Imaging Genetics Center, Laboratory of Neuro Imaging, University of California at Los Angeles School of Medicine, Los Angeles, CA 90095, USA.
Rajagopalan P Rajagopalan Priya P
Hua X Hua Xue X
Hibar DP Hibar Derrek P DP
Nir TM Nir Talia M TM
Toga AW Toga Arthur W AW
Jack CR Jr Jack Clifford R CR
Saykin AJ Saykin Andrew J AJ
Green RC Green Robert C RC
Weiner MW Weiner Michael W MW
Medland SE Medland Sarah E SE
Montgomery GW Montgomery Grant W GW
Hansell NK Hansell Narelle K NK
McMahon KL McMahon Katie L KL
de Zubicaray GI de Zubicaray Greig I GI
Martin NG Martin Nicholas G NG
Wright MJ Wright Margaret J MJ
Thompson PM Thompson Paul M PM
Alzheimer’s Disease Neuroimaging Initiative
INVESTIGATORS
LASTNAME FORENAME INITIALS AFFILIATION
Weiner Michael M
Aisen Paul P
Weiner Michael M
Aisen Paul P
Petersen Ronald R
Jack Clifford R CR
Jagust William W
Trojanowski John Q JQ
Toga Arthur W AW
Beckett Laurel L
Green Robert C RC
Saykin Andrew J AJ
Morris John J
Liu Enchi E
Green Robert C RC
Montine Tom T
Petersen Ronald R
Aisen Paul P
Gamst Anthony A
Thomas Ronald G RG
Donohue Michael M
Walter Sarah S
Gessert Devon D
Sather Tamie T
Beckett Laurel L
Harvey Danielle D
Gamst Anthony A
Donohue Michael M
Kornak John J
Jack Clifford R CR
Dale Anders A
Bernstein Matthew M
Felmlee Joel J
Fox Nick N
Thompson Paul P
Schuff Norbert N
Alexander Gene G
DeCarli Charles C
Jagust William W
Bandy Dan D
Koeppe Robert A RA
Foster Norm N
Reiman Eric M EM
Chen Kewei K
Mathis Chet C
Morris John J
Cairns Nigel J NJ
Taylor-Reinwald Lisa L
Trojanowki J Q JQ
Shaw Les L
Lee Virginia M Y VM
Korecka Magdalena M
Toga Arthur W AW
Crawford Karen K
Neu Scott S
Saykin Andrew J AJ
Foroud Tatiana M TM
Potkin Steven S
Shen Li L
Khachaturian Zaven Z
Frank Richard R
Snyder Peter J PJ
Molchan Susan S
Kaye Jeffrey J
Quinn Joseph J
Lind Betty B
Dolen Sara S
Schneider Lon S LS
Pawluczyk Sonia S
Spann Bryan M BM
Brewer James J
Vanderswag Helen H
Heidebrink Judith L JL
Lord Joanne L JL
Petersen Ronald R
Johnson Kris K
Doody Rachelle S RS
Villanueva-Meyer Javier J
Chowdhury Munir M
Stern Yaakov Y
Honig Lawrence S LS
Bell Karen L KL
Morris John C JC
Ances Beau B
Carroll Maria M
Leon Sue S
Mintun Mark A MA
Schneider Stacy S
Marson Daniel D
Griffith Randall R
Clark David D
Grossman Hillel H
Mitsis Effie E
Romirowsky Aliza A
deToledo-Morrell Leyla L
Shah Raj C RC
Duara Ranjan R
Varon Daniel D
Roberts Peggy P
Albert Marilyn M
Onyike Chiadi C
Kielb Stephanie S
Rusinek Henry H
de Leon Mony J MJ
Glodzik Lidia L
De Santi Susan S
Doraiswamy P Murali PM
Petrella Jeffrey R JR
Coleman R Edward RE
Arnold Steven E SE
Karlawish Jason H JH
Wolk David D
Smith Charles D CD
Jicha Greg G
Hardy Peter P
Lopez Oscar L OL
Oakley Maryann M
Simpson Donna M DM
Porsteinsson Anton P AP
Goldstein Bonnie S BS
Martin Kim K
Makino Kelly M KM
Ismail M Saleem MS
Brand Connie C
Mulnard Ruth A RA
Thai Gaby G
Mc-Adams-Ortiz Catherine C
Womack Kyle K
Mathews Dana D
Quiceno Mary M
Diaz-Arrastia Ramon R
King Richard R
Weiner Myron M
Martin-Cook Kristen K
DeVous Michael M
Levey Allan I AI
Lah James J JJ
Cellar Janet S JS
Burns Jeffrey M JM
Anderson Heather S HS
Swerdlow Russell H RH
Apostolova Liana L
Lu Po H PH
Bartzokis George G
Silverman Daniel H S DH
Graff-Radford Neill R NR
Parfitt Francine F
Johnson Heather H
Farlow Martin R MR
Hake Ann Marie AM
Matthews Brandy R BR
Herring Scott S
van Dyck Christopher H CH
Carson Richard E RE
MacAvoy Martha G MG
Chertkow Howard H
Bergman Howard H
Hosein Chris C
Black Sandra S
Stefanovic Bojana B
Caldwell Curtis C
Hsiung Ging-Yuek Robin GY
Feldman Howard H
Mudge Benita B
Assaly Michele M
Kertesz Andrew A
Rogers John J
Trost Dick D
Bernick Charles C
Munic Donna D
Kerwin Diana D
Mesulam Marek-Marsel MM
Lipowski Kristina K
Wu Chuang-Kuo CK
Johnson Nancy N
Sadowsky Carl C
Martinez Walter W
Villena Teresa T
Turner Raymond Scott RS
Johnson Kathleen K
Reynolds Brigid B
Sperling Reisa A RA
Johnson Keith A KA
Marshall Gad G
Frey Meghan M
Yesavage Jerome J
Taylor Joy L JL
Lane Barton B
Rosen Allyson A
Tinklenberg Jared J
Sabbagh Marwan M
Belden Christine C
Jacobson Sandra S
Kowall Neil N
Killiany Ronald R
Budson Andrew E AE
Norbash Alexander A
Johnson Patricia Lynn PL
Obisesan Thomas O TO
Wolday Saba S
Bwayo Salome K SK
Lerner Alan A
Hudson Leon L
Ogrocki Paula P
Fletcher Evan E
Carmichael Owen O
Olichney John J
DeCarli Charles C
Kittur Smita S
Borrie Michael M
Lee T-Y TY
Bartha Rob R
Johnson Sterling S
Asthana Sanjay S
Carlsson Cynthia M CM
Potkin Steven G SG
Preda Adrian A
Nguyen Dana D
Tariot Pierre P
Fleisher Adam A
Reeder Stephanie S
Bates Vernice V
Capote Horacio H
Rainka Michelle M
Scharre Douglas W DW
Kataki Maria M
Zimmerman Earl A EA
Celmins Dzintra D
Brown Alice D AD
Pearlson Godfrey D GD
Blank Karen K
Anderson Karen K
Saykin Andrew J AJ
Santulli Robert B RB
Schwartz Eben S ES
Sink Kaycee M KM
Williamson Jeff D JD
Garg Pradeep P
Watkins Franklin F
Ott Brian R BR
Querfurth Henry H
Tremont Geoffrey G
Salloway Stephen S
Malloy Paul P
Correia Stephen S
Rosen Howard J HJ
Miller Bruce L BL
Mintzer Jacobo J
Longmire Crystal Flynn CF
Spicer Kenneth K
Finger Elizabeth E
Rachinsky Irina I
Rogers John J
Kertesz Andrew A
Drost Dick D
JOURNAL
VOLUME: 110
ISSUE: 12
TITLE: Proceedings of the National Academy of Sciences of the United States of America
ISOABBREVIATION: Proc. Natl. Acad. Sci. U.S.A.
YEAR: 2013
MONTH: Mar
DAY: 19
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1091-6490
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Proc Natl Acad Sci U S A
COUNTRY: United States
ISSNLINKING: 0027-8424
NLMUNIQUEID: 7505876
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Clinical Trial
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Twin Study
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
AG027841 NIA NIH HHS United States
HG002213 NHGRI NIH HHS United States
HG006500 NHGRI NIH HHS United States
P41 EB015922 NIBIB NIH HHS United States
P50 AG005138 NIA NIH HHS United States
P50 AG008702 NIA NIH HHS United States
R01 AG040060 NIA NIH HHS United States
R01 EB007813 NIBIB NIH HHS United States
R01 EB008281 NIBIB NIH HHS United States
R01 EB008432 NIBIB NIH HHS United States
R01 HD050735 NICHD NIH HHS United States
R01 HG002213 NHGRI NIH HHS United States
R01 MH097268 NIMH NIH HHS United States
R01 NS080655 NINDS NIH HHS United States
T15 LM07356 NLM NIH HHS United States
U01 HG006500 NHGRI NIH HHS United States
U24 AG021886 NIA NIH HHS United States
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Adult
Alzheimer Disease genetics
Autistic Disorder radiography
Brain radiography
Chromosomes, Human, Pair 11 genetics
Endosomal Sorting Complexes Required for Transport genetics
Extracellular Matrix Proteins genetics
Female genetics
Genetic Variation genetics
Genome-Wide Association Study genetics
Humans genetics
Magnetic Resonance Imaging genetics
Male genetics
Severity of Illness Index genetics
Twins, Dizygotic genetics
Twins, Monozygotic genetics
Ubiquitin-Conjugating Enzymes genetics
Ubiquitin-Protein Ligases genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 Endosomal Sorting Complexes Required for Transport
0 Extracellular Matrix Proteins
0 SPON1 protein, human
EC 6.3.2.19 Nedd4 ubiquitin protein ligases
EC 6.3.2.19 UBE2A protein, human
EC 6.3.2.19 Ubiquitin-Conjugating Enzymes
EC 6.3.2.19 Ubiquitin-Protein Ligases
OTHER ID's
OTHERID SOURCE
PMC3606977 NLM