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| PMID |
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| TITLE |
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| can exceed SNP-based heritability. |
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| ABSTRACT |
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| In polygenic score (PGS) analysis, the coefficient of determination (R ) is a key statistic to evaluate efficacy. R is the proportion of phenotypic variance explained by the PGS, calculated in a cohort that is independent of the genome-wide association study (GWAS) that provided estimates of allelic effect sizes. The SNP-based heritability (h , the proportion of total phenotypic variances attributable to all common SNPs) is the theoretical upper limit of the out-of-sample prediction R . However, in real data analyses R has been reported to exceed h , which occurs in parallel with the observation that h estimates tend to decline as the number of cohorts being meta-analyzed increases. Here, we quantify why and when these observations are expected. Using theory and simulation, we show that if heterogeneities in cohort-specific h exist, or if genetic correlations between cohorts are less than one, h estimates can decrease as the number of cohorts being meta-analyzed increases. We derive conditions when the out-of-sample prediction R will be greater than h and show the validity of our derivations with real data from a binary trait (major depression) and a continuous trait (educational attainment). Our research calls for a better approach to integrating information from multiple cohorts to address issues of between-cohort heterogeneity. |
| Copyright © 2023 American Society of Human Genetics. 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 |
2023/02/06 |
| revised |
2023/06/05 |
| accepted |
2023/06/12 |
| pmc-release |
2024/01/06 |
| medline |
2023/07/10 06:42 |
| pubmed |
2023/06/29 01:08 |
| entrez |
2023/06/28 18:41 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Wang X |
|
Wang |
Xiaotong |
X |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. |
| Walker A |
|
Walker |
Alicia |
A |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. |
| Revez JA |
|
Revez |
Joana A |
JA |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. |
| Ni G |
|
Ni |
Guiyan |
G |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. |
| Adams MJ |
|
Adams |
Mark J |
MJ |
|
Division of Psychiatry, University of Edinburgh, Edinburgh, UK. |
| McIntosh AM |
|
McIntosh |
Andrew M |
AM |
|
Division of Psychiatry, University of Edinburgh, Edinburgh, UK; Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK. |
|
Major Depressive Disorder Working Group of the Psychiatric Genomics Consortium |
|
|
|
|
|
| Visscher PM |
|
Visscher |
Peter M |
PM |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia. Electronic address: peter.visscher@uq.edu.au. |
| Wray NR |
|
Wray |
Naomi R |
NR |
|
Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia; Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia. Electronic address: naomi.wray@uq.edu.au. |
|
| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Wray |
Naomi R |
NR |
|
| Ripke |
Stephan |
S |
|
| Mattheisen |
Manuel |
M |
|
| Trzaskowski |
Maciej |
M |
|
| Byrne |
Enda M |
EM |
|
| Abdellaoui |
Abdel |
A |
|
| Adams |
Mark J |
MJ |
|
| Agerbo |
Esben |
E |
|
| Air |
Tracy M |
TM |
|
| Andlauer |
Till F M |
TFM |
|
| Bacanu |
Silviu-Alin |
SA |
|
| Bækvad-Hansen |
Marie |
M |
|
| Beekman |
Aartjan T F |
ATF |
|
| Bigdeli |
Tim B |
TB |
|
| Binder |
Elisabeth B |
EB |
|
| Bryois |
Julien |
J |
|
| Buttenschøn |
Henriette N |
HN |
|
| Bybjerg-Grauholm |
Jonas |
J |
|
| Cai |
Na |
N |
|
| Castelao |
Enrique |
E |
|
| Christensen |
Jane Hvarregaard |
JH |
|
| Clarke |
Toni-Kim |
TK |
|
| Coleman |
Jonathan R I |
JRI |
|
| Colodro-Conde |
Lucía |
L |
|
| Couvy-Duchesne |
Baptiste |
B |
|
| Craddock |
Nick |
N |
|
| Crawford |
Gregory E |
GE |
|
| Davies |
Gail |
G |
|
| Degenhardt |
Franziska |
F |
|
| Derks |
Eske M |
EM |
|
| Direk |
Nese |
N |
|
| Dolan |
Conor V |
CV |
|
| Dunn |
Erin C |
EC |
|
| Eley |
Thalia C |
TC |
|
| Escott-Price |
Valentina |
V |
|
| Kiadeh |
Farnush Farhadi Hassan |
FFH |
|
| Finucane |
Hilary K |
HK |
|
| Foo |
Jerome C |
JC |
|
| Forstner |
Andreas J |
AJ |
|
| Frank |
Josef |
J |
|
| Gaspar |
Héléna A |
HA |
|
| Gill |
Michael |
M |
|
| Goes |
Fernando S |
FS |
|
| Gordon |
Scott D |
SD |
|
| Grove |
Jakob |
J |
|
| Hall |
Lynsey S |
LS |
|
| Søholm Hansen |
Christine |
C |
|
| Hansen |
Thomas F |
TF |
|
| Herms |
Stefan |
S |
|
| Hickie |
Ian B |
IB |
|
| Hoffmann |
Per |
P |
|
| Homuth |
Georg |
G |
|
| Horn |
Carsten |
C |
|
| Hottenga |
Jouke-Jan |
JJ |
|
| Hougaard |
David M |
DM |
|
| Howard |
David M |
DM |
|
| Ising |
Marcus |
M |
|
| Jansen |
Rick |
R |
|
| Jones |
Ian |
I |
|
| Jones |
Lisa A |
LA |
|
| Jorgenson |
Eric |
E |
|
| Knowles |
James A |
JA |
|
| Kohane |
Isaac S |
IS |
|
| Kraft |
Julia |
J |
|
| Kretzschmar |
Warren W |
WW |
|
| Kutalik |
Zoltán |
Z |
|
| Li |
Yihan |
Y |
|
| Lind |
Penelope A |
PA |
|
| MacIntyre |
Donald J |
DJ |
|
| MacKinnon |
Dean F |
DF |
|
| Maier |
Robert M |
RM |
|
| Maier |
Wolfgang |
W |
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| Marchini |
Jonathan |
J |
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| Mbarek |
Hamdi |
H |
|
| McGrath |
Patrick |
P |
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| McGuffin |
Peter |
P |
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| Medland |
Sarah E |
SE |
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| Mehta |
Divya |
D |
|
| Middeldorp |
Christel M |
CM |
|
| Mihailov |
Evelin |
E |
|
| Milaneschi |
Yuri |
Y |
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| Milani |
Lili |
L |
|
| Mondimore |
Francis M |
FM |
|
| Montgomery |
Grant W |
GW |
|
| Mostafavi |
Sara |
S |
|
| Mullins |
Niamh |
N |
|
| Nauck |
Matthias |
M |
|
| Ng |
Bernard |
B |
|
| Nivard |
Michel G |
MG |
|
| Nyholt |
Dale R |
DR |
|
| O'Reilly |
Paul F |
PF |
|
| Oskarsson |
Hogni |
H |
|
| Owen |
Michael J |
MJ |
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| Painter |
Jodie N |
JN |
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| Bøcker Pedersen |
Carsten |
C |
|
| Giørtz Pedersen |
Marianne |
M |
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| Peterson |
Roseann E |
RE |
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| Peyrot |
Wouter J |
WJ |
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| Pistis |
Giorgio |
G |
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| Posthuma |
Danielle |
D |
|
| Quiroz |
Jorge A |
JA |
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| Qvist |
Per |
P |
|
| Rice |
John P |
JP |
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| Riley |
Brien P |
BP |
|
| Rivera |
Margarita |
M |
|
| Saeed Mirza |
Saira |
S |
|
| Schoevers |
Robert |
R |
|
| Schulte |
Eva C |
EC |
|
| Shen |
Ling |
L |
|
| Shi |
Jianxin |
J |
|
| Shyn |
Stanley I |
SI |
|
| Sigurdsson |
Engilbert |
E |
|
| Sinnamon |
Grant C B |
GCB |
|
| Smit |
Johannes H |
JH |
|
| Smith |
Daniel J |
DJ |
|
| Stefansson |
Hreinn |
H |
|
| Steinberg |
Stacy |
S |
|
| Streit |
Fabian |
F |
|
| Strohmaier |
Jana |
J |
|
| Tansey |
Katherine E |
KE |
|
| Teismann |
Henning |
H |
|
| Teumer |
Alexander |
A |
|
| Thompson |
Wesley |
W |
|
| Thomson |
Pippa A |
PA |
|
| Thorgeirsson |
Thorgeir E |
TE |
|
| Traylor |
Matthew |
M |
|
| Treutlein |
Jens |
J |
|
| Trubetskoy |
Vassily |
V |
|
| Uitterlinden |
André G |
AG |
|
| Umbricht |
Daniel |
D |
|
| Van der Auwera |
Sandra |
S |
|
| van Hemert |
Albert M |
AM |
|
| Viktorin |
Alexander |
A |
|
| Visscher |
Peter M |
PM |
|
| Wang |
Yunpeng |
Y |
|
| Webb |
Bradley T |
BT |
|
| Weinsheimer |
Shantel Marie |
SM |
|
| Wellmann |
Jürgen |
J |
|
| Willemsen |
Gonneke |
G |
|
| Witt |
Stephanie H |
SH |
|
| Wu |
Yang |
Y |
|
| Xi |
Hualin S |
HS |
|
| Yang |
Jian |
J |
|
| Zhang |
Futao |
F |
|
| Arolt |
Volker |
V |
|
| Baune |
Bernhard T |
BT |
|
| Berger |
Klaus |
K |
|
| Boomsma |
Dorret I |
DI |
|
| Cichon |
Sven |
S |
|
| Dannlowski |
Udo |
U |
|
| de Geus |
E J C |
EJC |
|
| DePaulo |
J Raymond |
JR |
|
| Domenici |
Enrico |
E |
|
| Domschke |
Katharina |
K |
|
| Esko |
Tõnu |
T |
|
| Grabe |
Hans J |
HJ |
|
| Hamilton |
Steven P |
SP |
|
| Hayward |
Caroline |
C |
|
| Heath |
Andrew C |
AC |
|
| Kendler |
Kenneth S |
KS |
|
| Kloiber |
Stefan |
S |
|
| Lewis |
Glyn |
G |
|
| Li |
Qingqin S |
QS |
|
| Lucae |
Susanne |
S |
|
| Madden |
Pamela A F |
PAF |
|
| Magnusson |
Patrik K |
PK |
|
| Martin |
Nicholas G |
NG |
|
| McIntosh |
Andrew M |
AM |
|
| Metspalu |
Andres |
A |
|
| Mors |
Ole |
O |
|
| Bo Mortensen |
Preben |
P |
|
| Müller-Myhsok |
Bertram |
B |
|
| Nordentoft |
Merete |
M |
|
| Nöthen |
Markus M |
MM |
|
| O'Donovan |
Michael C |
MC |
|
| Paciga |
Sara A |
SA |
|
| Pedersen |
Nancy L |
NL |
|
| Penninx |
Brenda W J H |
BWJH |
|
| Perlis |
Roy H |
RH |
|
| Porteous |
David J |
DJ |
|
| Potash |
James B |
JB |
|
| Preisig |
Martin |
M |
|
| Rietschel |
Marcella |
M |
|
| Schaefer |
Catherine |
C |
|
| Schulze |
Thomas G |
TG |
|
| Smoller |
Jordan W |
JW |
|
| Stefansson |
Kari |
K |
|
| Tiemeier |
Henning |
H |
|
| Uher |
Rudolf |
R |
|
| Völzke |
Henry |
H |
|
| Weissman |
Myrna M |
MM |
|
| Werge |
Thomas |
T |
|
| Lewis |
Cathryn M |
CM |
|
| Levinson |
Douglas F |
DF |
|
| Breen |
Gerome |
G |
|
| Børglum |
Anders D |
AD |
|
| Sullivan |
Patrick F |
PF |
|
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| JOURNAL |
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| VOLUME: 110 |
| ISSUE: 7 |
| TITLE: American journal of human genetics |
| ISOABBREVIATION: Am J Hum Genet |
| YEAR: 2023 |
| MONTH: Jul |
| DAY: 06 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 1537-6605 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: Am J Hum Genet |
| COUNTRY: United States |
| ISSNLINKING: 0002-9297 |
| NLMUNIQUEID: 0370475 |
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| PUBLICATION TYPE |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
| Research Support, N.I.H., Extramural |
| Research Support, Non-U.S. Gov't |
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| COMMENTS AND CORRECTIONS |
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|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| R01 MH121545 |
NIMH NIH HHS |
United States |
| R01 MH124871 |
NIMH NIH HHS |
United States |
| U01 MH109528 |
NIMH NIH HHS |
United States |
| U01 MH109532 |
NIMH NIH HHS |
United States |
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| GENERAL NOTE |
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| KEYWORDS |
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| KEYWORD |
| SNP-based heritability |
| meta-analysis |
| out-of-sample prediction R(2) |
| polygenic risk prediction |
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| MESH HEADINGS |
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| DESCRIPTORNAME |
QUALIFIERNAME |
| Humans |
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| Genome-Wide Association Study |
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| Polymorphism, Single Nucleotide |
genetics |
| Multifactorial Inheritance |
genetics |
| Phenotype |
genetics |
| Computer Simulation |
genetics |
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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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|
