Genome scan meta-analysis of schizophrenia and bipolar disorder, part II: Schizophrenia.
Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
Lewis
Cathryn M
CM
Division of Genetics and Development, Guy's, King's & St Thomas' School of Medicine, London, UK.
Levinson
Douglas F
DF
Wise
Lesley H
LH
DeLisi
Lynn E
LE
Straub
Richard E
RE
Hovatta
Iiris
I
Williams
Nigel M
NM
Schwab
Sibylle G
SG
Pulver
Ann E
AE
Faraone
Stephen V
SV
Brzustowicz
Linda M
LM
Kaufmann
Charles A
CA
Garver
David L
DL
Gurling
Hugh M D
HM
Lindholm
Eva
E
Coon
Hilary
H
Moises
Hans W
HW
Byerley
William
W
Shaw
Sarah H
SH
Mesen
Andrea
A
Sherrington
Robin
R
O'Neill
F Anthony
FA
Walsh
Dermot
D
Kendler
Kenneth S
KS
Ekelund
Jesper
J
Paunio
Tiina
T
Lönnqvist
Jouko
J
Peltonen
Leena
L
O'Donovan
Michael C
MC
Owen
Michael J
MJ
Wildenauer
Dieter B
DB
Maier
Wolfgang
W
Nestadt
Gerald
G
Blouin
Jean-Louis
JL
Antonarakis
Stylianos E
SE
Mowry
Bryan J
BJ
Silverman
Jeremy M
JM
Crowe
Raymond R
RR
Cloninger
C Robert
CR
Tsuang
Ming T
MT
Malaspina
Dolores
D
Harkavy-Friedman
Jill M
JM
Svrakic
Dragan M
DM
Bassett
Anne S
AS
Holcomb
Jennifer
J
Kalsi
Gursharan
G
McQuillin
Andrew
A
Brynjolfson
Jon
J
Sigmundsson
Thordur
T
Petursson
Hannes
H
Jazin
Elena
E
Zoëga
Tomas
T
Helgason
Tomas
T
D001714:Bipolar Disorder / Q000235:genetics*; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D012559:Schizophrenia / Q000235:genetics*