|
|
| PMID |
|
|
| TITLE |
|
| Meta-analysis of gene-level associations for rare variants based on single-variant statistics. |
|
| ABSTRACT |
|
|
|
| Meta-analysis of genome-wide association studies (GWASs) has led to the discoveries of many common variants associated with complex human diseases. There is a growing recognition that identifying "causal" rare variants also requires large-scale meta-analysis. The fact that association tests with rare variants are performed at the gene level rather than at the variant level poses unprecedented challenges in the meta-analysis. First, different studies may adopt different gene-level tests, so the results are not compatible. Second, gene-level tests require multivariate statistics (i.e., components of the test statistic and their covariance matrix), which are difficult to obtain. To overcome these challenges, we propose to perform gene-level tests for rare variants by combining the results of single-variant analysis (i.e., p values of association tests and effect estimates) from participating studies. This simple strategy is possible because of an insight that multivariate statistics can be recovered from single-variant statistics, together with the correlation matrix of the single-variant test statistics, which can be estimated from one of the participating studies or from a publicly available database. We show both theoretically and numerically that the proposed meta-analysis approach provides accurate control of the type I error and is as powerful as joint analysis of individual participant data. This approach accommodates any disease phenotype and any study design and produces all commonly used gene-level tests. An application to the GWAS summary results of the Genetic Investigation of ANthropometric Traits (GIANT) consortium reveals rare and low-frequency variants associated with human height. The relevant software is freely available. |
| Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. |
|
| DATE PUBLISHED |
|
|
| HISTORY |
|
| PUBSTATUS |
PUBSTATUSDATE |
| received |
2013/04/30 |
| revised |
2013/06/05 |
| accepted |
2013/06/12 |
| entrez |
2013/07/30 06:00 |
| pubmed |
2013/07/31 06:00 |
| medline |
2013/12/18 06:00 |
|
| AUTHORS |
|
| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Hu YJ |
|
Hu |
Yi-Juan |
YJ |
|
Department of Biostatistics and Bioinformatics, Emory University, Atlanta, GA 30322, USA. |
| Berndt SI |
|
Berndt |
Sonja I |
SI |
|
|
| Gustafsson S |
|
Gustafsson |
Stefan |
S |
|
|
| Ganna A |
|
Ganna |
Andrea |
A |
|
|
|
Genetic Investigation of ANthropometric Traits (GIANT) Consortium |
|
|
|
|
|
| Hirschhorn J |
|
Hirschhorn |
Joel |
J |
|
|
| North KE |
|
North |
Kari E |
KE |
|
|
| Ingelsson E |
|
Ingelsson |
Erik |
E |
|
|
| Lin DY |
|
Lin |
Dan-Yu |
DY |
|
|
|
| INVESTIGATORS |
|
| LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
| Berndt |
Sonja I |
SI |
|
| Gustafsson |
Stefan |
S |
|
| Mägi |
Reedik |
R |
|
| Ganna |
Andrea |
A |
|
| Wheeler |
Eleanor |
E |
|
| Feitosa |
Mary F |
MF |
|
| Justice |
Anne E |
AE |
|
| Monda |
Keri L |
KL |
|
| Croteau-Chonka |
Damien C |
DC |
|
| Day |
Felix R |
FR |
|
| Esko |
Tõnu |
T |
|
| Fall |
Tove |
T |
|
| Ferreira |
Teresa |
T |
|
| Gentilini |
Davide |
D |
|
| Jackson |
Anne U |
AU |
|
| Luan |
Jian'an |
J |
|
| Randall |
Joshua C |
JC |
|
| Vedantam |
Sailaja |
S |
|
| Willer |
Cristen J |
CJ |
|
| Winkler |
Thomas W |
TW |
|
| Wood |
Andrew R |
AR |
|
| Workalemahu |
Tsegaselassie |
T |
|
| Hu |
Yi-Juan |
YJ |
|
| Lee |
Sang Hong |
SH |
|
| Liang |
Liming |
L |
|
| Lin |
Dan-Yu |
DY |
|
| Min |
Josine L |
JL |
|
| Neale |
Benjamin M |
BM |
|
| Thorleifsson |
Gudmar |
G |
|
| Yang |
Jian |
J |
|
| Albrecht |
Eva |
E |
|
| Amin |
Najaf |
N |
|
| Bragg-Gresham |
Jennifer L |
JL |
|
| Cadby |
Gemma |
G |
|
| den Heijer |
Martin |
M |
|
| Eklund |
Niina |
N |
|
| Fischer |
Krista |
K |
|
| Goel |
Anuj |
A |
|
| Hottenga |
Jouke-Jan |
JJ |
|
| Huffman |
Jennifer E |
JE |
|
| Jarick |
Ivonne |
I |
|
| Johansson |
Åsa |
Å |
|
| Johnson |
Toby |
T |
|
| Kanoni |
Stavroula |
S |
|
| Kleber |
Marcus E |
ME |
|
| König |
Inke R |
IR |
|
| Kristiansson |
Kati |
K |
|
| Kutalik |
Zoltán |
Z |
|
| Lamina |
Claudia |
C |
|
| Lecoeur |
Cecile |
C |
|
| Li |
Guo |
G |
|
| Mangino |
Massimo |
M |
|
| McArdle |
Wendy L |
WL |
|
| Medina-Gomez |
Carolina |
C |
|
| Müller-Nurasyid |
Martina |
M |
|
| Ngwa |
Julius S |
JS |
|
| Nolte |
Ilja M |
IM |
|
| Paternoster |
Lavinia |
L |
|
| Pechlivanis |
Sonali |
S |
|
| Perola |
Markus |
M |
|
| Peters |
Marjolein J |
MJ |
|
| Preuss |
Michael |
M |
|
| Rose |
Lynda M |
LM |
|
| Shi |
Jianxin |
J |
|
| Shungin |
Dmitry |
D |
|
| Smith |
Albert Vernon |
AV |
|
| Strawbridge |
Rona J |
RJ |
|
| Surakka |
Ida |
I |
|
| Teumer |
Alexander |
A |
|
| Trip |
Mieke D |
MD |
|
| Tyrer |
Jonathan |
J |
|
| Van Vliet-Ostaptchouk |
Jana V |
JV |
|
| Vandenput |
Liesbeth |
L |
|
| Waite |
Lindsay L |
LL |
|
| Zhao |
Jing Hua |
JH |
|
| Absher |
Devin |
D |
|
| Asselbergs |
Folkert W |
FW |
|
| Atalay |
Mustafa |
M |
|
| Attwood |
Antony P |
AP |
|
| Balmforth |
Anthony J |
AJ |
|
| Basart |
Hanneke |
H |
|
| Beilby |
John |
J |
|
| Bonnycastle |
Lori L |
LL |
|
| Brambilla |
Paolo |
P |
|
| Bruinenberg |
Marcel |
M |
|
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Harry |
H |
|
| Chasman |
Daniel I |
DI |
|
| Chines |
Peter S |
PS |
|
| Collins |
Francis S |
FS |
|
| Connell |
John M |
JM |
|
| Cookson |
William |
W |
|
| de Faire |
Ulf |
U |
|
| de Vegt |
Femmie |
F |
|
| Dei |
Mariano |
M |
|
| Dimitriou |
Maria |
M |
|
| Edkins |
Sarah |
S |
|
| Estrada |
Karol |
K |
|
| Evans |
David M |
DM |
|
| Farrall |
Martin |
M |
|
| Ferrario |
Marco M |
MM |
|
| Ferrières |
Jean |
J |
|
| Franke |
Lude |
L |
|
| Frau |
Francesca |
F |
|
| Gejman |
Pablo V |
PV |
|
| Grallert |
Harald |
H |
|
| Grönberg |
Henrik |
H |
|
| Gudnason |
Vilmundur |
V |
|
| Hall |
Alistair S |
AS |
|
| Hall |
Per |
P |
|
| Hartikainen |
Anna-Liisa |
AL |
|
| Hayward |
Caroline |
C |
|
| Heard-Costa |
Nancy L |
NL |
|
| Heath |
Andrew C |
AC |
|
| Hebebrand |
Johannes |
J |
|
| Homuth |
Georg |
G |
|
| Hu |
Frank B |
FB |
|
| Hunt |
Sarah E |
SE |
|
| Hyppönen |
Elina |
E |
|
| Iribarren |
Carlos |
C |
|
| Jacobs |
Kevin B |
KB |
|
| Jansson |
John-Olov |
JO |
|
| Jula |
Antti |
A |
|
| Kähönen |
Mika |
M |
|
| Kathiresan |
Sekar |
S |
|
| Kee |
Frank |
F |
|
| Khaw |
Kay-Tee |
KT |
|
| Kivimaki |
Mika |
M |
|
| Koenig |
Wolfgang |
W |
|
| Kraja |
Aldi T |
AT |
|
| Kumari |
Meena |
M |
|
| Kuulasmaa |
Kari |
K |
|
| Kuusisto |
Johanna |
J |
|
| Laitinen |
Jaana H |
JH |
|
| Lakka |
Timo A |
TA |
|
| Langenberg |
Claudia |
C |
|
| Launer |
Lenore J |
LJ |
|
| Lind |
Lars |
L |
|
| Lindström |
Jaana |
J |
|
| Liu |
Jianjun |
J |
|
| Liuzzi |
Antonio |
A |
|
| Lokki |
Marja-Liisa |
ML |
|
| Lorentzon |
Mattias |
M |
|
| Madden |
Pamela A |
PA |
|
| Magnusson |
Patrik K |
PK |
|
| Manunta |
Paolo |
P |
|
| Marek |
Diana |
D |
|
| März |
Winfried |
W |
|
| Mateo Leach |
Irene |
I |
|
| McKnight |
Barbara |
B |
|
| Medland |
Sarah E |
SE |
|
| Mihailov |
Evelin |
E |
|
| Milani |
Lili |
L |
|
| Montgomery |
Grant W |
GW |
|
| Mooser |
Vincent |
V |
|
| Mühleisen |
Thomas W |
TW |
|
| Munroe |
Patricia B |
PB |
|
| Musk |
Arthur W |
AW |
|
| Narisu |
Narisu |
N |
|
| Navis |
Gerjan |
G |
|
| Nicholson |
George |
G |
|
| Nohr |
Ellen A |
EA |
|
| Ong |
Ken K |
KK |
|
| Oostra |
Ben A |
BA |
|
| Palmer |
Colin N A |
CN |
|
| Palotie |
Aarno |
A |
|
| Peden |
John F |
JF |
|
| Pedersen |
Nancy |
N |
|
| Peters |
Annette |
A |
|
| Polasek |
Ozren |
O |
|
| Pouta |
Anneli |
A |
|
| Pramstaller |
Peter P |
PP |
|
| Prokopenko |
Inga |
I |
|
| Pütter |
Carolin |
C |
|
| Radhakrishnan |
Aparna |
A |
|
| Raitakari |
Olli |
O |
|
| Rendon |
Augusto |
A |
|
| Rivadeneira |
Fernando |
F |
|
| Rudan |
Igor |
I |
|
| Saaristo |
Timo E |
TE |
|
| Sambrook |
Jennifer G |
JG |
|
| Sanders |
Alan R |
AR |
|
| Sanna |
Serena |
S |
|
| Saramies |
Jouko |
J |
|
| Schipf |
Sabine |
S |
|
| Schreiber |
Stefan |
S |
|
| Schunkert |
Heribert |
H |
|
| Shin |
So-Youn |
SY |
|
| Signorini |
Stefano |
S |
|
| Sinisalo |
Juha |
J |
|
| Skrobek |
Boris |
B |
|
| Soranzo |
Nicole |
N |
|
| Stančáková |
Alena |
A |
|
| Stark |
Klaus |
K |
|
| Stephens |
Jonathan C |
JC |
|
| Stirrups |
Kathleen |
K |
|
| Stolk |
Ronald P |
RP |
|
| Stumvoll |
Michael |
M |
|
| Swift |
Amy J |
AJ |
|
| Theodoraki |
Eirini V |
EV |
|
| Thorand |
Barbara |
B |
|
| Tregouet |
David-Alexandre |
DA |
|
| Tremoli |
Elena |
E |
|
| Van der Klauw |
Melanie M |
MM |
|
| van Meurs |
Joyce B J |
JB |
|
| Vermeulen |
Sita H |
SH |
|
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Jorma |
J |
|
| Virtamo |
Jarmo |
J |
|
| Vitart |
Veronique |
V |
|
| Waeber |
Gérard |
G |
|
| Wang |
Zhaoming |
Z |
|
| Widén |
Elisabeth |
E |
|
| Wild |
Sarah H |
SH |
|
| Willemsen |
Gonneke |
G |
|
| Winkelmann |
Bernhard R |
BR |
|
| Witteman |
Jacqueline C M |
JC |
|
| Wolffenbuttel |
Bruce H R |
BH |
|
| Wong |
Andrew |
A |
|
| Wright |
Alan F |
AF |
|
| Zillikens |
M Carola |
MC |
|
| Amouyel |
Philippe |
P |
|
| Boehm |
Bernhard O |
BO |
|
| Boerwinkle |
Eric |
E |
|
| Boomsma |
Dorret I |
DI |
|
| Caulfield |
Mark J |
MJ |
|
| Chanock |
Stephen J |
SJ |
|
| Cupples |
L Adrienne |
LA |
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Daniele |
D |
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George V |
GV |
|
| Erdmann |
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J |
|
| Eriksson |
Johan G |
JG |
|
| Franks |
Paul W |
PW |
|
| Froguel |
Philippe |
P |
|
| Gieger |
Christian |
C |
|
| Gyllensten |
Ulf |
U |
|
| Hamsten |
Anders |
A |
|
| Harris |
Tamara B |
TB |
|
| Hengstenberg |
Christian |
C |
|
| Hicks |
Andrew A |
AA |
|
| Hingorani |
Aroon |
A |
|
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Anke |
A |
|
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Albert |
A |
|
| Hovingh |
Kees G |
KG |
|
| Hveem |
Kristian |
K |
|
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Thomas |
T |
|
| Jarvelin |
Marjo-Riitta |
MR |
|
| Jöckel |
Karl-Heinz |
KH |
|
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Sirkka M |
SM |
|
| Kiemeney |
Lambertus A |
LA |
|
| Kuh |
Diana |
D |
|
| Laakso |
Markku |
M |
|
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Terho |
T |
|
| Levinson |
Douglas F |
DF |
|
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Nicholas G |
NG |
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Andres |
A |
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Andrew D |
AD |
|
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AJ |
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LJ |
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PM |
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Veikko |
V |
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Nilesh J |
NJ |
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Harold |
H |
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Thorkild I A |
TI |
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Timothy D |
TD |
|
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Kari |
K |
|
| Tönjes |
Anke |
A |
|
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Jaakko |
J |
|
| Uitterlinden |
André G |
AG |
|
| Uusitupa |
Matti |
M |
|
| van der Harst |
Pim |
P |
|
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Peter |
P |
|
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Henri |
H |
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NJ |
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HE |
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JF |
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GR |
|
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TL |
|
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Michael |
M |
|
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Ingrid B |
IB |
|
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Panos |
P |
|
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Caroline S |
CS |
|
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Timothy |
T |
|
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Leif C |
LC |
|
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Talin |
T |
|
| Heid |
Iris M |
IM |
|
| Hunter |
David |
D |
|
| Kaplan |
Robert C |
RC |
|
| Karpe |
Fredrik |
F |
|
| Moffatt |
Miriam |
M |
|
| Mohlke |
Karen L |
KL |
|
| O'Connell |
Jeffrey R |
JR |
|
| Pawitan |
Yudi |
Y |
|
| Schadt |
Eric E |
EE |
|
| Schlessinger |
David |
D |
|
| Steinthorsdottir |
Valgerdur |
V |
|
| Strachan |
David P |
DP |
|
| Thorsteinsdottir |
Unnur |
U |
|
| van Duijn |
Cornelia M |
CM |
|
| Visscher |
Peter M |
PM |
|
| Di Blasio |
Anna Maria |
AM |
|
| Hirschhorn |
Joel N |
JN |
|
| Lindgren |
Cecilia M |
CM |
|
| Morris |
Andrew P |
AP |
|
| Meyre |
David |
D |
|
| Scherag |
André |
A |
|
| McCarthy |
Mark I |
MI |
|
| Speliotes |
Elizabeth K |
EK |
|
| North |
Kari E |
KE |
|
| Loos |
Ruth J F |
RJ |
|
| Ingelsson |
Erik |
E |
|
|
| JOURNAL |
|
| VOLUME: 93 |
| ISSUE: 2 |
| TITLE: American journal of human genetics |
| ISOABBREVIATION: Am J Hum Genet |
| YEAR: 2013 |
| MONTH: Aug |
| DAY: 08 |
| 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 |
| Meta-Analysis |
| Research Support, N.I.H., Extramural |
| Research Support, N.I.H., Intramural |
|
| COMMENTS AND CORRECTIONS |
|
| REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
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|
| Cites |
Proc Natl Acad Sci U S A. 2013 Jul 23;110(30):12247-52 |
23847208 |
|
|
| GRANTS |
|
| GRANTID |
AGENCY |
COUNTRY |
| R01 CA082659 |
NCI NIH HHS |
United States |
| HHSN268201100012C |
NHLBI NIH HHS |
United States |
| UL1RR025005 |
NCRR NIH HHS |
United States |
| K05 AA017688 |
NIAAA NIH HHS |
United States |
| R01HL59367 |
NHLBI NIH HHS |
United States |
| HHSN268201100010C |
NHLBI NIH HHS |
United States |
| UL1 RR025005 |
NCRR NIH HHS |
United States |
| HHSN26820110009C |
PHS HHS |
United States |
| R01 HL059367 |
NHLBI NIH HHS |
United States |
| R01CA082659 |
NCI NIH HHS |
United States |
| HHSN268201100011I |
NHLBI NIH HHS |
United States |
| HHSN268201100011C |
NHLBI NIH HHS |
United States |
| R01 HL086694 |
NHLBI NIH HHS |
United States |
| G1000143 |
Medical Research Council |
United Kingdom |
| U01HG004803 |
NHGRI NIH HHS |
United States |
| HHSN268200625226C |
PHS HHS |
United States |
| U01 HG004402 |
NHGRI NIH HHS |
United States |
| R01 DK075787 |
NIDDK NIH HHS |
United States |
| HHSN268201100010C |
PHS HHS |
United States |
| U01HG004402 |
NHGRI NIH HHS |
United States |
| HHSN26820110006C |
PHS HHS |
United States |
| 097117 |
Wellcome Trust |
United Kingdom |
|
Intramural NIH HHS |
United States |
| HHSN26820110007C |
PHS HHS |
United States |
| 14136 |
Cancer Research UK |
United Kingdom |
| HHSN26820110008C |
PHS HHS |
United States |
| HHSN268201100012C |
PHS HHS |
United States |
| R01HL087641 |
NHLBI NIH HHS |
United States |
| U01 HG004803 |
NHGRI NIH HHS |
United States |
| G0401527 |
Medical Research Council |
United Kingdom |
| HHSN26820110005C |
PHS HHS |
United States |
| 090532 |
Wellcome Trust |
United Kingdom |
| MC_PC_U127561128 |
Medical Research Council |
United Kingdom |
| MR/K013351/1 |
Medical Research Council |
United Kingdom |
| HHSN268201100011C |
PHS HHS |
United States |
| P01CA142538 |
NCI NIH HHS |
United States |
| P01 CA142538 |
NCI NIH HHS |
United States |
| R01 HL087641 |
NHLBI NIH HHS |
United States |
| HHSN26800625226C |
PHS HHS |
United States |
| R01HL086694 |
NHLBI NIH HHS |
United States |
|
| GENERAL NOTE |
|
|
| KEYWORDS |
|
|
| MESH HEADINGS |
|
| DESCRIPTORNAME |
QUALIFIERNAME |
| Computer Simulation |
|
| Gene Frequency |
|
| Genetic Variation |
|
| Genome-Wide Association Study |
|
| Genotype |
|
| Humans |
|
| Models, Genetic |
|
| Phenotype |
|
| Polymorphism, Single Nucleotide |
|
| Receptors, LDL |
genetics |
| Receptors, Odorant |
genetics |
| Software |
genetics |
|
| SUPPLEMENTARY MESH |
|
|
| GENE SYMBOLS |
|
|
| CHEMICALS |
|
| REGISTRYNUMBER |
NAMEOFSUBSTANCE |
| 0 |
LDLR protein, human |
| 0 |
Receptors, LDL |
| 0 |
Receptors, Odorant |
|
| OTHER ID's |
|
|
|
