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| PMID |
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| TITLE |
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| Psychiatric disorders converge on common pathways but diverge in cellular context, spatial distribution, and directionality of genetic effects. |
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| ABSTRACT |
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| Psychiatric conditions share common genes, but mechanisms that differentiate diagnoses remain unclear. We present a multidimensional framework for functional analysis of rare copy number variants (CNVs) across 6 diagnostic categories, including schizophrenia (SCZ), autism (ASD), bipolar disorder (BD), depression (MDD), PTSD, and ADHD (N = 574,965). Using gene-set burden analysis (GSBA), we tested duplication (DUP) and deletion (DEL) burden across 2,645 functional gene sets defined by the intersections of pathways, cell types, and cortical regions. While diagnoses converge on shared pathways, mixed-effects modeling revealed divergence of pathway effects by cell type, brain region, and gene dosage. Factor analysis identified latent dimensions aligned with clinical axes. A primary factor (F1) captured reciprocal dose-dependent effects of DUP and DEL in SCZ reflecting positive and negative effects in excitatory versus inhibitory neurons and association versus sensory cortex. SCZ and ASD were both strongly aligned with F1 but with opposing directionalities. Orthogonal factors highlighted neuronal versus non-neuronal effects in mood disorders (F2) and differential spatial distributions of DEL effects in ADHD and MDD (F3). High-impact CNVs at 16p11.2 and 22q11.2 were enriched for combinations of cell-type-specific genes involved in pathways consistent with our broader findings. These results reveal molecular and cellular mechanisms that are broadly shared across psychiatric traits but differ between diagnostic categories in context and directionality. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| medline |
2025/08/12 11:16 |
| pubmed |
2025/08/12 11:15 |
| entrez |
2025/08/12 05:15 |
| pmc-release |
2025/08/11 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Engchuan W |
|
Engchuan |
Worrawat |
W |
|
|
| Shanta O |
|
Shanta |
Omar |
O |
|
|
| Kumar K |
|
Kumar |
Kuldeep |
K |
|
|
| MacDonald JR |
|
MacDonald |
Jeffrey R |
JR |
|
|
| Thiruvahindrapuram B |
|
Thiruvahindrapuram |
Bhooma |
B |
|
|
| Hamdan O |
|
Hamdan |
Omar |
O |
|
|
| Klein M |
|
Klein |
Marieke |
M |
|
|
| Maihofer A |
|
Maihofer |
Adam |
A |
|
|
| Guevara J |
|
Guevara |
James |
J |
|
|
| Hong O |
|
Hong |
Oanh |
O |
|
|
| Huguet G |
|
Huguet |
Guillaume |
G |
|
|
| Sacks M |
|
Sacks |
Molly |
M |
|
|
| Ahangari M |
|
Ahangari |
Mohammad |
M |
|
|
| Feitosa RMMW |
|
Feitosa |
Rayssa M M W |
RMMW |
|
|
| Han K |
|
Han |
Kara |
K |
|
|
| Mendes M |
|
Mendes |
Marla |
M |
|
|
| Zhou X |
|
Zhou |
Xiaopu |
X |
|
|
| Bautista NX |
|
Bautista |
Nelson X |
NX |
|
|
| Pellecchia G |
|
Pellecchia |
Giovanna |
G |
|
|
| Wang Z |
|
Wang |
Zhouzhi |
Z |
|
|
| Merico D |
|
Merico |
Daniele |
D |
|
|
| Yuen RKC |
|
Yuen |
Ryan K C |
RKC |
|
|
| Trost B |
|
Trost |
Brett |
B |
|
|
| Sønderby I |
|
Sønderby |
Ida |
I |
|
|
| Adams MJ |
|
Adams |
Mark J |
MJ |
|
|
| Adolfsson R |
|
Adolfsson |
Rolf |
R |
|
|
| Agartz I |
|
Agartz |
Ingrid |
I |
|
|
| Aiello AE |
|
Aiello |
Allison E |
AE |
|
|
| Alda M |
|
Alda |
Martin |
M |
|
|
| Allardyce J |
|
Allardyce |
Judith |
J |
|
|
| Amstadter AB |
|
Amstadter |
Ananda B |
AB |
|
|
| Andlauer TFM |
|
Andlauer |
Till F M |
TFM |
|
|
| Andreassen OA |
|
Andreassen |
Ole A |
OA |
|
|
| Artigas MS |
|
Artigas |
María S |
MS |
|
|
| Austin SB |
|
Austin |
S Bryn |
SB |
|
|
| Ayub M |
|
Ayub |
Muhammad |
M |
|
|
| Baker DG |
|
Baker |
Dewleen G |
DG |
|
|
| Bass N |
|
Bass |
Nick |
N |
|
|
| Baune BT |
|
Baune |
Bernhard T |
BT |
|
|
| Bayas M |
|
Bayas |
Maximilian |
M |
|
|
| Berger K |
|
Berger |
Klaus |
K |
|
|
| Biernacka JM |
|
Biernacka |
Joanna M |
JM |
|
|
| Bigdeli T |
|
Bigdeli |
Tim |
T |
|
|
| Bisson JI |
|
Bisson |
Jonathan I |
JI |
|
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| Blackwood D |
|
Blackwood |
Douglas |
D |
|
|
| Boks M |
|
Boks |
Marco |
M |
|
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| Braff D |
|
Braff |
David |
D |
|
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| Bramon E |
|
Bramon |
Elvira |
E |
|
|
| Breen G |
|
Breen |
Gerome |
G |
|
|
| Brueckl T |
|
Brueckl |
Tanja |
T |
|
|
| Bryant RA |
|
Bryant |
Richard A |
RA |
|
|
| Bulik CM |
|
Bulik |
Cynthia M |
CM |
|
|
| Buxbaum J |
|
Buxbaum |
Joseph |
J |
|
|
| Cairns MJ |
|
Cairns |
Murray J |
MJ |
|
|
| Caldas-de-Almeida JM |
|
Caldas-de-Almeida |
Jose M |
JM |
|
|
| Campbell M |
|
Campbell |
Megan |
M |
|
|
| Campion D |
|
Campion |
Dominique |
D |
|
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| Carr VJ |
|
Carr |
Vaughan J |
VJ |
|
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| Castelao E |
|
Castelao |
Enrique |
E |
|
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| Chaumette B |
|
Chaumette |
Boris |
B |
|
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| Cichon S |
|
Cichon |
Sven |
S |
|
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| Cohen D |
|
Cohen |
David |
D |
|
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| Corvin A |
|
Corvin |
Aiden |
A |
|
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| Craddock N |
|
Craddock |
Nicholas |
N |
|
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| Crosbie J |
|
Crosbie |
Jennifer |
J |
|
|
| Czamara D |
|
Czamara |
Darrina |
D |
|
|
| Dannlowski U |
|
Dannlowski |
Udo |
U |
|
|
| Degenhardt F |
|
Degenhardt |
Franziska |
F |
|
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| Delahanty DL |
|
Delahanty |
Douglas L |
DL |
|
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| Dempfle A |
|
Dempfle |
Astrid |
A |
|
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| Desachy G |
|
Desachy |
Guillaume |
G |
|
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| Di Florio A |
|
Di Florio |
Arianna |
A |
|
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| Dickerson FB |
|
Dickerson |
Faith B |
FB |
|
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| Djurovic S |
|
Djurovic |
Srdjan |
S |
|
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| Domschke K |
|
Domschke |
Katharina |
K |
|
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| Douglas L |
|
Douglas |
Lisa |
L |
|
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| Drange OK |
|
Drange |
Ole K |
OK |
|
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| Duncan LE |
|
Duncan |
Laramie E |
LE |
|
|
| Edenberg HJ |
|
Edenberg |
Howard J |
HJ |
|
|
| Esko T |
|
Esko |
Tonu |
T |
|
|
| Faraone S |
|
Faraone |
Steve |
S |
|
|
| Feeny NC |
|
Feeny |
Norah C |
NC |
|
|
| Forstner AJ |
|
Forstner |
Andreas J |
AJ |
|
|
| Franke B |
|
Franke |
Barbara |
B |
|
|
| Frye M |
|
Frye |
Mark |
M |
|
|
| Fu DJ |
|
Fu |
Dong-Jing |
DJ |
|
|
| Fullerton JM |
|
Fullerton |
Janice M |
JM |
|
|
| Gareeva A |
|
Gareeva |
Anna |
A |
|
|
| Garvert L |
|
Garvert |
Linda |
L |
|
|
| Gatt JM |
|
Gatt |
Justine M |
JM |
|
|
| Gejman P |
|
Gejman |
Pablo |
P |
|
|
| Geschwind DH |
|
Geschwind |
Daniel H |
DH |
|
|
| Giegling I |
|
Giegling |
Ina |
I |
|
|
| Glatt SJ |
|
Glatt |
Stephen J |
SJ |
|
|
| Glessner J |
|
Glessner |
Joe |
J |
|
|
| Goes FS |
|
Goes |
Fernando S |
FS |
|
|
| Gordon-Smith K |
|
Gordon-Smith |
Katherine |
K |
|
|
| Grabe H |
|
Grabe |
Hans |
H |
|
|
| Green MJ |
|
Green |
Melissa J |
MJ |
|
|
| Green MF |
|
Green |
Michael F |
MF |
|
|
| Greenwood T |
|
Greenwood |
Tiffany |
T |
|
|
| Grigoroiu-Serbanescu M |
|
Grigoroiu-Serbanescu |
Maria |
M |
|
|
| Gur RE |
|
Gur |
Raquel E |
RE |
|
|
| Gur RC |
|
Gur |
Ruben C |
RC |
|
|
| Guzman-Parra J |
|
Guzman-Parra |
Jose |
J |
|
|
| Haavik J |
|
Haavik |
Jan |
J |
|
|
| Hahn T |
|
Hahn |
Tim |
T |
|
|
| Hakonarson H |
|
Hakonarson |
Hakon |
H |
|
|
| Hallmayer J |
|
Hallmayer |
Joachim |
J |
|
|
| Hamshere ML |
|
Hamshere |
Marian L |
ML |
|
|
| Hartmann AM |
|
Hartmann |
Annette M |
AM |
|
|
| Hassan A |
|
Hassan |
Arsalan |
A |
|
|
| Hayward C |
|
Hayward |
Caroline |
C |
|
|
| Hebebrand J |
|
Hebebrand |
Johannes |
J |
|
|
| Hemmings SMJ |
|
Hemmings |
Sian M J |
SMJ |
|
|
| Herms S |
|
Herms |
Stefan |
S |
|
|
| Herrera-Rivero M |
|
Herrera-Rivero |
Marisol |
M |
|
|
| Hinney A |
|
Hinney |
Anke |
A |
|
|
| Homuth G |
|
Homuth |
Georg |
G |
|
|
| Ingason A |
|
Ingason |
Andrés |
A |
|
|
| Ito LT |
|
Ito |
Lucas T |
LT |
|
|
| Iwata N |
|
Iwata |
Nakao |
N |
|
|
| Jones I |
|
Jones |
Ian |
I |
|
|
| Jones LA |
|
Jones |
Lisa A |
LA |
|
|
| Jonsson L |
|
Jonsson |
Lina |
L |
|
|
| Jönsson EG |
|
Jönsson |
Erik G |
EG |
|
|
| Kahn RS |
|
Kahn |
René S |
RS |
|
|
| Karlsson R |
|
Karlsson |
Robert |
R |
|
|
| Kaufman ML |
|
Kaufman |
Milissa L |
ML |
|
|
| Kelsoe JR |
|
Kelsoe |
John R |
JR |
|
|
| Kennedy JL |
|
Kennedy |
James L |
JL |
|
|
| King A |
|
King |
Anthony |
A |
|
|
| Kircher T |
|
Kircher |
Tilo |
T |
|
|
| Kirov G |
|
Kirov |
George |
G |
|
|
| Knappskog P |
|
Knappskog |
Per |
P |
|
|
| Knowles JA |
|
Knowles |
James A |
JA |
|
|
| Kobayashi N |
|
Kobayashi |
Nene |
N |
|
|
| Koenen KC |
|
Koenen |
Karestan C |
KC |
|
|
| Konte B |
|
Konte |
Bettina |
B |
|
|
| Korgaonkar M |
|
Korgaonkar |
Mayuresh |
M |
|
|
| Kowalec K |
|
Kowalec |
Kaarina |
K |
|
|
| Krebs MO |
|
Krebs |
Marie-Odile |
MO |
|
|
| Landén M |
|
Landén |
Mikael |
M |
|
|
| Laurent-Levinson C |
|
Laurent-Levinson |
Claudine |
C |
|
|
| Lebois LA |
|
Lebois |
Lauren A |
LA |
|
|
| Levinson D |
|
Levinson |
Doug |
D |
|
|
| Lewis C |
|
Lewis |
Cathryn |
C |
|
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| Li Q |
|
Li |
Qingqin |
Q |
|
|
| Liberzon I |
|
Liberzon |
Israel |
I |
|
|
| Light G |
|
Light |
Greg |
G |
|
|
| Loo SK |
|
Loo |
Sandra K |
SK |
|
|
| Lu Y |
|
Lu |
Yi |
Y |
|
|
| Lucae S |
|
Lucae |
Susanne |
S |
|
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| Marmar C |
|
Marmar |
Charles |
C |
|
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| Martin NG |
|
Martin |
Nicholas G |
NG |
|
|
| Mayoral F |
|
Mayoral |
Fermin |
F |
|
|
| McIntosh AM |
|
McIntosh |
Andrew M |
AM |
|
|
| McLaughlin KA |
|
McLaughlin |
Katie A |
KA |
|
|
| McLean SA |
|
McLean |
Samuel A |
SA |
|
|
| McQuillin A |
|
McQuillin |
Andrew |
A |
|
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| Medland SE |
|
Medland |
Sarah E |
SE |
|
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| Meyer-Lindenberg A |
|
Meyer-Lindenberg |
Andreas |
A |
|
|
| Milanova V |
|
Milanova |
Vihra |
V |
|
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| Mitchell PB |
|
Mitchell |
Philip B |
PB |
|
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| Molina E |
|
Molina |
Esther |
E |
|
|
| Mowry B |
|
Mowry |
Bryan |
B |
|
|
| Muller-Myhsok B |
|
Muller-Myhsok |
Bertram |
B |
|
|
| Mullins N |
|
Mullins |
Niamh |
N |
|
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| Murray R |
|
Murray |
Robin |
R |
|
|
| Nöthen MM |
|
Nöthen |
Markus M |
MM |
|
|
| Nurnberger JI |
|
Nurnberger |
John I |
JI |
|
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| O'Connell KS |
|
O'Connell |
Kevin S |
KS |
|
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| Ophoff RA |
|
Ophoff |
Roel A |
RA |
|
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| Orcutt HK |
|
Orcutt |
Holly K |
HK |
|
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| Owen MJ |
|
Owen |
Michael J |
MJ |
|
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| Palotie A |
|
Palotie |
Aarno |
A |
|
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| Pato C |
|
Pato |
Carlos |
C |
|
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| Pato M |
|
Pato |
Michele |
M |
|
|
| Pawlak J |
|
Pawlak |
Joanna |
J |
|
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|
Peters |
Triinu |
T |
|
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| Petryshen TL |
|
Petryshen |
Tracey L |
TL |
|
|
| Pistis G |
|
Pistis |
Giorgio |
G |
|
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| Potash JB |
|
Potash |
James B |
JB |
|
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| Powell J |
|
Powell |
John |
J |
|
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| Preisig M |
|
Preisig |
Martin |
M |
|
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| Quested D |
|
Quested |
Digby |
D |
|
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| Ramos-Quiroga JA |
|
Ramos-Quiroga |
Josep A |
JA |
|
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| Reif A |
|
Reif |
Andreas |
A |
|
|
| Ressler KJ |
|
Ressler |
Kerry J |
KJ |
|
|
| Ribasés M |
|
Ribasés |
Marta |
M |
|
|
| Rietschel M |
|
Rietschel |
Marcella |
M |
|
|
| Risbrough VB |
|
Risbrough |
Victoria B |
VB |
|
|
| Rivera M |
|
Rivera |
Margarita |
M |
|
|
| Rothbaum AO |
|
Rothbaum |
Alex O |
AO |
|
|
| Rothbaum BO |
|
Rothbaum |
Barbara O |
BO |
|
|
| Rujescu D |
|
Rujescu |
Dan |
D |
|
|
| Saito T |
|
Saito |
Takeo |
T |
|
|
| Sanders AR |
|
Sanders |
Alan R |
AR |
|
|
| Schachar RJ |
|
Schachar |
Russell J |
RJ |
|
|
| Schofield PR |
|
Schofield |
Peter R |
PR |
|
|
| Schulte EC |
|
Schulte |
Eva C |
EC |
|
|
| Schulze TG |
|
Schulze |
Thomas G |
TG |
|
|
| Scott LJ |
|
Scott |
Laura J |
LJ |
|
|
| Seedat S |
|
Seedat |
Soraya |
S |
|
|
| Sheerin C |
|
Sheerin |
Christina |
C |
|
|
| Shi J |
|
Shi |
Jianxin |
J |
|
|
| Sklar P |
|
Sklar |
Pamela |
P |
|
|
| Smalley S |
|
Smalley |
Susan |
S |
|
|
| Smeland OB |
|
Smeland |
Olav B |
OB |
|
|
| Smoller JW |
|
Smoller |
Jordan W |
JW |
|
|
| Sonuga-Barke E |
|
Sonuga-Barke |
Edmund |
E |
|
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| St Clair D |
|
St Clair |
David |
D |
|
|
| Steen NE |
|
Steen |
Nils Eiel |
NE |
|
|
| Stein D |
|
Stein |
Dan |
D |
|
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| Stein F |
|
Stein |
Frederike |
F |
|
|
| Stein MB |
|
Stein |
Murray B |
MB |
|
|
| Streit F |
|
Streit |
Fabian |
F |
|
|
| Swerdlow N |
|
Swerdlow |
Neal |
N |
|
|
| Thibaut F |
|
Thibaut |
Florence |
F |
|
|
| Thygesen JH |
|
Thygesen |
Johan H |
JH |
|
|
| Timerbulatov I |
|
Timerbulatov |
Ilgiz |
I |
|
|
| Toma C |
|
Toma |
Claudio |
C |
|
|
| Trapido E |
|
Trapido |
Edward |
E |
|
|
| Tremblay M |
|
Tremblay |
Micheline |
M |
|
|
| Tsuang MT |
|
Tsuang |
Ming T |
MT |
|
|
| Uddin M |
|
Uddin |
Monica |
M |
|
|
| Vawter MP |
|
Vawter |
Marquis P |
MP |
|
|
| Vincent JB |
|
Vincent |
John B |
JB |
|
|
| Völzke H |
|
Völzke |
Henry |
H |
|
|
| Walters JT |
|
Walters |
James T |
JT |
|
|
| Weickert CS |
|
Weickert |
Cynthia S |
CS |
|
|
| Weiss LA |
|
Weiss |
Lauren A |
LA |
|
|
| Weissman MM |
|
Weissman |
Myrna M |
MM |
|
|
| Werge T |
|
Werge |
Thomas |
T |
|
|
| Witt SH |
|
Witt |
Stephanie H |
SH |
|
|
| Xavier M |
|
Xavier |
Miguel |
M |
|
|
| Yolken R |
|
Yolken |
Robert |
R |
|
|
| Young RM |
|
Young |
Ross M |
RM |
|
|
| Zayats T |
|
Zayats |
Tetyana |
T |
|
|
| Zoellner LA |
|
Zoellner |
Lori A |
LA |
|
|
|
AGP Consortium |
|
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|
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|
PEIC Psychosis Endophenotypes International Consortium |
|
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ADHD Working Group of the Psychiatric Genomics Consortium |
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Autism Working Group of the Psychiatric Genomics Consortium |
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Bipolar Disorder Working Group of the Psychiatric Genomics Consortium |
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Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium |
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PTSD Working Group of the Psychiatric Genomics Consortium |
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Schizophrenia Working Group of the Psychiatric Genomics Consortium |
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CNV Working Group of the Psychiatric Genomics Consortium |
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| Kendall K |
|
Kendall |
Kimberley |
K |
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| Riley B |
|
Riley |
Brien |
B |
|
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| Wray NR |
|
Wray |
Naomi R |
NR |
|
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| O'Donovan MC |
|
O'Donovan |
Michael C |
MC |
|
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| Sullivan PF |
|
Sullivan |
Patrick F |
PF |
|
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| Sanchez-Roige S |
|
Sanchez-Roige |
Sandra |
S |
|
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| Nievergelt CM |
|
Nievergelt |
Caroline M |
CM |
|
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| Jacquemont S |
|
Jacquemont |
Sébastien |
S |
|
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| Scherer SW |
|
Scherer |
Stephen W |
SW |
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| Sebat J |
|
Sebat |
Jonathan |
J |
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| INVESTIGATORS |
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| JOURNAL |
|
| VOLUME: |
| ISSUE: |
| TITLE: medRxiv : the preprint server for health sciences |
| ISOABBREVIATION: medRxiv |
| YEAR: 2025 |
| MONTH: Jul |
| DAY: 16 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: |
| ISSNTYPE: |
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| MEDLINE JOURNAL |
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| MEDLINETA: medRxiv |
| COUNTRY: United States |
| ISSNLINKING: |
| NLMUNIQUEID: 101767986 |
|
| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
| Preprint |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
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| GENERAL NOTE |
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| KEYWORDS |
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| MESH HEADINGS |
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| SUPPLEMENTARY MESH |
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| GENE SYMBOLS |
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| CHEMICALS |
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| OTHER ID's |
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