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| PMID |
|
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| TITLE |
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| Joint analysis of psychiatric disorders increases accuracy of risk prediction for schizophrenia, bipolar disorder, and major depressive disorder. |
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| ABSTRACT |
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| Genetic risk prediction has several potential applications in medical research and clinical practice and could be used, for example, to stratify a heterogeneous population of patients by their predicted genetic risk. However, for polygenic traits, such as psychiatric disorders, the accuracy of risk prediction is low. Here we use a multivariate linear mixed model and apply multi-trait genomic best linear unbiased prediction for genetic risk prediction. This method exploits correlations between disorders and simultaneously evaluates individual risk for each disorder. We show that the multivariate approach significantly increases the prediction accuracy for schizophrenia, bipolar disorder, and major depressive disorder in the discovery as well as in independent validation datasets. By grouping SNPs based on genome annotation and fitting multiple random effects, we show that the prediction accuracy could be further improved. The gain in prediction accuracy of the multivariate approach is equivalent to an increase in sample size of 34% for schizophrenia, 68% for bipolar disorder, and 76% for major depressive disorders using single trait models. Because our approach can be readily applied to any number of GWAS datasets of correlated traits, it is a flexible and powerful tool to maximize prediction accuracy. With current sample size, risk predictors are not useful in a clinical setting but already are a valuable research tool, for example in experimental designs comparing cases with high and low polygenic risk. |
| Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| received |
2014/10/23 |
| accepted |
2014/12/08 |
| entrez |
2015/02/03 06:00 |
| pubmed |
2015/02/03 06:00 |
| medline |
2015/04/10 06:00 |
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| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Maier R |
|
Maier |
Robert |
R |
|
The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. |
| Moser G |
|
Moser |
Gerhard |
G |
|
The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. |
| Chen GB |
|
Chen |
Guo-Bo |
GB |
|
The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. |
| Ripke S |
|
Ripke |
Stephan |
S |
|
Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. |
|
Cross-Disorder Working Group of the Psychiatric Genomics Consortium |
|
|
|
|
|
| Coryell W |
|
Coryell |
William |
W |
|
Department of Psychiatry, University of Iowa, Iowa City, IA 52242, USA. |
| Potash JB |
|
Potash |
James B |
JB |
|
Department of Psychiatry, University of Iowa, Iowa City, IA 52242, USA. |
| Scheftner WA |
|
Scheftner |
William A |
WA |
|
Department of Psychiatry, Rush University Medical Center, Chicago, IL 60612, USA. |
| Shi J |
|
Shi |
Jianxin |
J |
|
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA. |
| Weissman MM |
|
Weissman |
Myrna M |
MM |
|
Department of Psychiatry, Columbia University, and New York State Psychiatric Institute, New York, NY 10032, USA. |
| Hultman CM |
|
Hultman |
Christina M |
CM |
|
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden. |
| Landén M |
|
Landén |
Mikael |
M |
|
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 77, Sweden; Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the Gothenburg University, 413 45 Gothenburg, Sweden. |
| Levinson DF |
|
Levinson |
Douglas F |
DF |
|
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, CA 94305, USA. |
| Kendler KS |
|
Kendler |
Kenneth S |
KS |
|
Virginia Institute for Psychiatric and Behavioral Genetics, Department of Psychiatry, Virginia Commonwealth University, Richmond, VA 23298, USA. |
| Smoller JW |
|
Smoller |
Jordan W |
JW |
|
Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA. |
| Wray NR |
|
Wray |
Naomi R |
NR |
|
The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. |
| Lee SH |
|
Lee |
S Hong |
SH |
|
The Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia. Electronic address: hong.lee@uq.edu.au. |
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| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Absher |
Devin |
D |
|
| Agartz |
Ingrid |
I |
|
| Akil |
Huda |
H |
|
| Amin |
Farooq |
F |
|
| Andreassen |
Ole A |
OA |
|
| Anjorin |
Adebayo |
A |
|
| Anney |
Richard |
R |
|
| Arking |
Dan E |
DE |
|
| Asherson |
Philip |
P |
|
| Azevedo |
Maria H |
MH |
|
| Backlund |
Lena |
L |
|
| Badner |
Judith A |
JA |
|
| Bailey |
Anthony J |
AJ |
|
| Banaschewski |
Tobias |
T |
|
| Barchas |
Jack D |
JD |
|
| Barnes |
Michael R |
MR |
|
| Barrett |
Thomas B |
TB |
|
| Bass |
Nicholas |
N |
|
| Battaglia |
Agatino |
A |
|
| Bauer |
Michael |
M |
|
| Bayés |
Mònica |
M |
|
| Bellivier |
Frank |
F |
|
| Bergen |
Sarah E |
SE |
|
| Berrettini |
Wade |
W |
|
| Betancur |
Catalina |
C |
|
| Bettecken |
Thomas |
T |
|
| Biederman |
Joseph |
J |
|
| Binder |
Elisabeth B |
EB |
|
| Black |
Donald W |
DW |
|
| Blackwood |
Douglas H R |
DH |
|
| Bloss |
Cinnamon S |
CS |
|
| Boehnke |
Michael |
M |
|
| Boomsma |
Dorret I |
DI |
|
| Breen |
Gerome |
G |
|
| Breuer |
René |
R |
|
| Bruggeman |
Richard |
R |
|
| Buccola |
Nancy G |
NG |
|
| Buitelaar |
Jan K |
JK |
|
| Bunney |
William E |
WE |
|
| Buxbaum |
Joseph D |
JD |
|
| Byerley |
William F |
WF |
|
| Caesar |
Sian |
S |
|
| Cahn |
Wiepke |
W |
|
| Cantor |
Rita M |
RM |
|
| Casas |
Miguel |
M |
|
| Chakravarti |
Aravinda |
A |
|
| Chambert |
Kimberly |
K |
|
| Choudhury |
Khalid |
K |
|
| Cichon |
Sven |
S |
|
| Cloninger |
C Robert |
CR |
|
| Collier |
David A |
DA |
|
| Cook |
Edwin H |
EH |
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| Coon |
Hilary |
H |
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| Cormand |
Bru |
B |
|
| Cormican |
Paul |
P |
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| Corvin |
Aiden |
A |
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| Coryell |
William H |
WH |
|
| Craddock |
Nicholas |
N |
|
| Craig |
David W |
DW |
|
| Craig |
Ian W |
IW |
|
| Crosbie |
Jennifer |
J |
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| Cuccaro |
Michael L |
ML |
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| Curtis |
David |
D |
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| Czamara |
Darina |
D |
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| Daly |
Mark J |
MJ |
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| Datta |
Susmita |
S |
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| Dawson |
Geraldine |
G |
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| Day |
Richard |
R |
|
| De Geus |
Eco J |
EJ |
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| Degenhardt |
Franziska |
F |
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| Devlin |
Bernie |
B |
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| Djurovic |
Srdjan |
S |
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| Donohoe |
Gary J |
GJ |
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| Doyle |
Alysa E |
AE |
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| Duan |
Jubao |
J |
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| Dudbridge |
Frank |
F |
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| Duketis |
Eftichia |
E |
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| Ebstein |
Richard P |
RP |
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| Edenberg |
Howard J |
HJ |
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| Elia |
Josephine |
J |
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| Ennis |
Sean |
S |
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| Etain |
Bruno |
B |
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| Fanous |
Ayman |
A |
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| Faraone |
Stephen V |
SV |
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| Farmer |
Anne E |
AE |
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| Ferrier |
I Nicol |
IN |
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| Flickinger |
Matthew |
M |
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| Fombonne |
Eric |
E |
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| Foroud |
Tatiana |
T |
|
| Frank |
Josef |
J |
|
| Franke |
Barbara |
B |
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| Fraser |
Christine |
C |
|
| Freedman |
Robert |
R |
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| Freimer |
Nelson B |
NB |
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| Freitag |
Christine M |
CM |
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| Friedl |
Marion |
M |
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| Frisén |
Louise |
L |
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| Gallagher |
Louise |
L |
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| Gejman |
Pablo V |
PV |
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| Georgieva |
Lyudmila |
L |
|
| Gershon |
Elliot S |
ES |
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| Geschwind |
Daniel H |
DH |
|
| Giegling |
Ina |
I |
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| Gill |
Michael |
M |
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| Gordon |
Scott D |
SD |
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| Gordon-Smith |
Katherine |
K |
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| Green |
Elaine K |
EK |
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| Greenwood |
Tiffany A |
TA |
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| Grice |
Dorothy E |
DE |
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| Gross |
Magdalena |
M |
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| Grozeva |
Detelina |
D |
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| Guan |
Weihua |
W |
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| Gurling |
Hugh |
H |
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| De Haan |
Lieuwe |
L |
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| Haines |
Jonathan L |
JL |
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| Hakonarson |
Hakon |
H |
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| Hallmayer |
Joachim |
J |
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| Hamilton |
Steven P |
SP |
|
| Hamshere |
Marian L |
ML |
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| Hansen |
Thomas F |
TF |
|
| Hartmann |
Annette M |
AM |
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| Hautzinger |
Martin |
M |
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| Heath |
Andrew C |
AC |
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| Henders |
Anjali K |
AK |
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| Herms |
Stefan |
S |
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| Hickie |
Ian B |
IB |
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| Hipolito |
Maria |
M |
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| Hoefels |
Susanne |
S |
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| Holmans |
Peter A |
PA |
|
| Holsboer |
Florian |
F |
|
| Hoogendijk |
Witte J |
WJ |
|
| Hottenga |
Jouke-Jan |
JJ |
|
| Hultman |
Christina M |
CM |
|
| Hus |
Vanessa |
V |
|
| Ingason |
Andrés |
A |
|
| Ising |
Marcus |
M |
|
| Jamain |
Stéphane |
S |
|
| Jones |
Ian |
I |
|
| Jones |
Lisa |
L |
|
| Kähler |
Anna K |
AK |
|
| Kahn |
René S |
RS |
|
| Kandaswamy |
Radhika |
R |
|
| Keller |
Matthew C |
MC |
|
| Kelsoe |
John R |
JR |
|
| Kendler |
Kenneth S |
KS |
|
| Kennedy |
James L |
JL |
|
| Kenny |
Elaine |
E |
|
| Kent |
Lindsey |
L |
|
| Kim |
Yunjung |
Y |
|
| Kirov |
George K |
GK |
|
| Klauck |
Sabine M |
SM |
|
| Klei |
Lambertus |
L |
|
| Knowles |
James A |
JA |
|
| Kohli |
Martin A |
MA |
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| Koller |
Daniel L |
DL |
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| Konte |
Bettina |
B |
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| Korszun |
Ania |
A |
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| Krabbendam |
Lydia |
L |
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| Krasucki |
Robert |
R |
|
| Kuntsi |
Jonna |
J |
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| Kwan |
Phoenix |
P |
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| Landén |
Mikael |
M |
|
| Långström |
Niklas |
N |
|
| Lathrop |
Mark |
M |
|
| Lawrence |
Jacob |
J |
|
| Lawson |
William B |
WB |
|
| Leboyer |
Marion |
M |
|
| Ledbetter |
David H |
DH |
|
| Lee |
Phil H |
PH |
|
| Lencz |
Todd |
T |
|
| Lesch |
Klaus-Peter |
KP |
|
| Levinson |
Douglas F |
DF |
|
| Lewis |
Cathryn M |
CM |
|
| Li |
Jun |
J |
|
| Lichtenstein |
Paul |
P |
|
| Lieberman |
Jeffrey A |
JA |
|
| Lin |
Dan-Yu |
DY |
|
| Linszen |
Don H |
DH |
|
| Liu |
Chunyu |
C |
|
| Lohoff |
Falk W |
FW |
|
| Loo |
Sandra K |
SK |
|
| Lord |
Catherine |
C |
|
| Lowe |
Jennifer K |
JK |
|
| Lucae |
Susanne |
S |
|
| MacIntyre |
Donald J |
DJ |
|
| Madden |
Pamela A F |
PA |
|
| Maestrini |
Elena |
E |
|
| Magnusson |
Patrik K E |
PK |
|
| Mahon |
Pamela B |
PB |
|
| Maier |
Wolfgang |
W |
|
| Malhotra |
Anil K |
AK |
|
| Mane |
Shrikant M |
SM |
|
| Martin |
Christa L |
CL |
|
| Martin |
Nicholas G |
NG |
|
| Mattheisen |
Manuel |
M |
|
| Matthews |
Keith |
K |
|
| Mattingsdal |
Morten |
M |
|
| McCarroll |
Steven A |
SA |
|
| McGhee |
Kevin A |
KA |
|
| McGough |
James J |
JJ |
|
| McGrath |
Patrick J |
PJ |
|
| McGuffin |
Peter |
P |
|
| McInnis |
Melvin G |
MG |
|
| McIntosh |
Andrew |
A |
|
| McKinney |
Rebecca |
R |
|
| McLean |
Alan W |
AW |
|
| McMahon |
Francis J |
FJ |
|
| McMahon |
William M |
WM |
|
| McQuillin |
Andrew |
A |
|
| Medeiros |
Helena |
H |
|
| Medland |
Sarah E |
SE |
|
| Meier |
Sandra |
S |
|
| Melle |
Ingrid |
I |
|
| Meng |
Fan |
F |
|
| Meyer |
Jobst |
J |
|
| Middeldorp |
Christel M |
CM |
|
| Middleton |
Lefkos |
L |
|
| Milanova |
Vihra |
V |
|
| Miranda |
Ana |
A |
|
| Monaco |
Anthony P |
AP |
|
| Montgomery |
Grant W |
GW |
|
| Moran |
Jennifer L |
JL |
|
| Moreno-De-Luca |
Daniel |
D |
|
| Morken |
Gunnar |
G |
|
| Morris |
Derek W |
DW |
|
| Morrow |
Eric M |
EM |
|
| Moskvina |
Valentina |
V |
|
| Mowry |
Bryan J |
BJ |
|
| Muglia |
Pierandrea |
P |
|
| Mühleisen |
Thomas W |
TW |
|
| Müller-Myhsok |
Bertram |
B |
|
| Murtha |
Michael |
M |
|
| Myers |
Richard M |
RM |
|
| Myin-Germeys |
Inez |
I |
|
| Neale |
Benjamin M |
BM |
|
| Nelson |
Stan F |
SF |
|
| Nievergelt |
Caroline M |
CM |
|
| Nikolov |
Ivan |
I |
|
| Nimgaonkar |
Vishwajit |
V |
|
| Nolen |
Willem A |
WA |
|
| Nöthen |
Markus M |
MM |
|
| Nurnberger |
John I |
JI |
|
| Nwulia |
Evaristus A |
EA |
|
| Nyholt |
Dale R |
DR |
|
| O'Donovan |
Michael C |
MC |
|
| O'Dushlaine |
Colm |
C |
|
| Oades |
Robert D |
RD |
|
| Olincy |
Ann |
A |
|
| Oliveira |
Guiomar |
G |
|
| Olsen |
Line |
L |
|
| Ophoff |
Roel A |
RA |
|
| Osby |
Urban |
U |
|
| Owen |
Michael J |
MJ |
|
| Palotie |
Aarno |
A |
|
| Parr |
Jeremy R |
JR |
|
| Paterson |
Andrew D |
AD |
|
| Pato |
Carlos N |
CN |
|
| Pato |
Michele T |
MT |
|
| Penninx |
Brenda W |
BW |
|
| Pergadia |
Michele L |
ML |
|
| Pericak-Vance |
Margaret A |
MA |
|
| Perlis |
Roy H |
RH |
|
| Pickard |
Benjamin S |
BS |
|
| Pimm |
Jonathan |
J |
|
| Piven |
Joseph |
J |
|
| Posthuma |
Danielle |
D |
|
| Potash |
James B |
JB |
|
| Poustka |
Fritz |
F |
|
| Propping |
Peter |
P |
|
| Purcell |
Shaun M |
SM |
|
| Puri |
Vinay |
V |
|
| Quested |
Digby J |
DJ |
|
| Quinn |
Emma M |
EM |
|
| Ramos-Quiroga |
Josep Antoni |
JA |
|
| Rasmussen |
Henrik B |
HB |
|
| Raychaudhuri |
Soumya |
S |
|
| Rehnström |
Karola |
K |
|
| Reif |
Andreas |
A |
|
| Ribasés |
Marta |
M |
|
| Rice |
John P |
JP |
|
| Rietschel |
Marcella |
M |
|
| Ripke |
Stephan |
S |
|
| Roeder |
Kathryn |
K |
|
| Roeyers |
Herbert |
H |
|
| Rossin |
Lizzy |
L |
|
| Rothenberger |
Aribert |
A |
|
| Rouleau |
Guy |
G |
|
| Ruderfer |
Douglas |
D |
|
| Rujescu |
Dan |
D |
|
| Sanders |
Alan R |
AR |
|
| Sanders |
Stephan J |
SJ |
|
| Santangelo |
Susan L |
SL |
|
| Schachar |
Russell |
R |
|
| Schalling |
Martin |
M |
|
| Schatzberg |
Alan F |
AF |
|
| Scheftner |
William A |
WA |
|
| Schellenberg |
Gerard D |
GD |
|
| Scherer |
Stephen W |
SW |
|
| Schork |
Nicholas J |
NJ |
|
| Schulze |
Thomas G |
TG |
|
| Schumacher |
Johannes |
J |
|
| Schwarz |
Markus |
M |
|
| Scolnick |
Edward |
E |
|
| Scott |
Laura J |
LJ |
|
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Joseph A |
JA |
|
| Shi |
Jianxin |
J |
|
| Shilling |
Paul D |
PD |
|
| Shyn |
Stanley I |
SI |
|
| Silverman |
Jeremy M |
JM |
|
| Sklar |
Pamela |
P |
|
| Slager |
Susan L |
SL |
|
| Smalley |
Susan L |
SL |
|
| Smit |
Johannes H |
JH |
|
| Smith |
Erin N |
EN |
|
| Smoller |
Jordan W |
JW |
|
| Sonuga-Barke |
Edmund J S |
EJ |
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| St Clair |
David |
D |
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| State |
Matthew |
M |
|
| Steffens |
Michael |
M |
|
| Steinhausen |
Hans-Christoph |
HC |
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| Strauss |
John S |
JS |
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| Strohmaier |
Jana |
J |
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| Stroup |
T Scott |
TS |
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| Sullivan |
Patrick F |
PF |
|
| Sutcliffe |
James |
J |
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| Szatmari |
Peter |
P |
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| Szelinger |
Szabocls |
S |
|
| Thapar |
Anita |
A |
|
| Thirumalai |
Srinivasa |
S |
|
| Thompson |
Robert C |
RC |
|
| Todorov |
Alexandre A |
AA |
|
| Tozzi |
Federica |
F |
|
| Treutlein |
Jens |
J |
|
| Tzeng |
Jung-Ying |
JY |
|
| Uhr |
Manfred |
M |
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| van den Oord |
Edwin J C G |
EJ |
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| Van Grootheest |
Gerard |
G |
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| Van Os |
Jim |
J |
|
| Vicente |
Astrid M |
AM |
|
| Vieland |
Veronica J |
VJ |
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| Vincent |
John B |
JB |
|
| Visscher |
Peter M |
PM |
|
| Walsh |
Christopher A |
CA |
|
| Wassink |
Thomas H |
TH |
|
| Watson |
Stanley J |
SJ |
|
| Weiss |
Lauren A |
LA |
|
| Weissman |
Myrna M |
MM |
|
| Werge |
Thomas |
T |
|
| Wienker |
Thomas F |
TF |
|
| Wiersma |
Durk |
D |
|
| Wijsman |
Ellen M |
EM |
|
| Willemsen |
Gonneke |
G |
|
| Williams |
Nigel |
N |
|
| Willsey |
A Jeremy |
AJ |
|
| Witt |
Stephanie H |
SH |
|
| Wray |
Naomi R |
NR |
|
| Xu |
Wei |
W |
|
| Young |
Allan H |
AH |
|
| Yu |
Timothy W |
TW |
|
| Zammit |
Stanley |
S |
|
| Zandi |
Peter P |
PP |
|
| Zhang |
Peng |
P |
|
| Zitman |
Frans G |
FG |
|
| Zöllner |
Sebastian |
S |
|
|
| JOURNAL |
|
| VOLUME: 96 |
| ISSUE: 2 |
| TITLE: American journal of human genetics |
| ISOABBREVIATION: Am J Hum Genet |
| YEAR: 2015 |
| MONTH: Feb |
| DAY: 05 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1537-6605 |
| ISSNTYPE: Electronic |
|
| MEDLINE JOURNAL |
|
| MEDLINETA: Am J Hum Genet |
| COUNTRY: United States |
| ISSNLINKING: 0002-9297 |
| NLMUNIQUEID: 0370475 |
|
| PUBLICATION TYPE |
|
| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
| Cites |
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|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| D43 TW009114 |
FIC NIH HHS |
United States |
| R01 MH060912 |
NIMH NIH HHS |
United States |
| P01 GM099568 |
NIGMS NIH HHS |
United States |
| R01 MH059541 |
NIMH NIH HHS |
United States |
| UL1 TR000142 |
NCATS NIH HHS |
United States |
| R01 MH061686 |
NIMH NIH HHS |
United States |
| P30 CA016359 |
NCI NIH HHS |
United States |
| MR/L010305/1 |
Medical Research Council |
United Kingdom |
| G0800509 |
Medical Research Council |
United Kingdom |
| R01 MH090553 |
NIMH NIH HHS |
United States |
| R01 MH059552 |
NIMH NIH HHS |
United States |
| G0300189 |
Medical Research Council |
United Kingdom |
| U01 MH085520 |
NIMH NIH HHS |
United States |
| G1000708 |
Medical Research Council |
United Kingdom |
| R01 MH077139 |
NIMH NIH HHS |
United States |
| 104036 |
Wellcome Trust |
United Kingdom |
| R01 MH063480 |
NIMH NIH HHS |
United States |
| R01 MH094293 |
NIMH NIH HHS |
United States |
| R01 MH059542 |
NIMH NIH HHS |
United States |
| R25 MH060482 |
NIMH NIH HHS |
United States |
| R01 MH075131 |
NIMH NIH HHS |
United States |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Bipolar Disorder |
genetics |
| Depressive Disorder, Major |
genetics |
| Genetic Testing |
methods |
| Genetics, Medical |
methods |
| Humans |
methods |
| Linear Models |
methods |
| Mental Disorders |
genetics |
| Multifactorial Inheritance |
genetics |
| Multivariate Analysis |
genetics |
| Polymorphism, Single Nucleotide |
genetics |
| Risk Assessment |
methods |
| Schizophrenia |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
|
| OTHER ID's |
|
|
|
