TY - JOUR
TI - Genome-Wide Association Study of Multiplex Schizophrenia Pedigrees
AU - Levinson, Douglas F.
AU - Shi, Jianxin
AU - Wang, Kai
AU - Oh, Sang and
AU - Riley, Brien
AU - Pulver, Ann E.
AU - Wildenauer, Dieter B.
AU - Laurent,
AU - Claudine
AU - Mowry, Bryan J.
AU - Gejman, Pablo V.
AU - Owen, Michael J.
AU - and Kendler, Kenneth S.
AU - Nestadt, Gerald
AU - Schwab, Sibylle G. and
AU - Mallet, Jacques
AU - Nertney, Deborah
AU - Sanders, Alan R.
AU - Williams,
AU - Nigel M.
AU - Wormley, Brandon
AU - Lasseter, Virginia K.
AU - Albus,
AU - Margot
AU - Godard-Bauche, Stephanie
AU - Alexander, Madeline
AU - Duan,
AU - Jubao
AU - O'Donovan, Michael C.
AU - Walsh, Dermot
AU - O'Neill, Anthony
AU - and Papadimitriou, George N.
AU - Dikeos, Dimitris
AU - Maier, Wolfgang
AU - and Lerer, Bernard
AU - Campion, Dominique
AU - Cohen, David
AU - Jay,
AU - Maurice
AU - Fanous, Ayman
AU - Eichhammer, Peter
AU - Silverman, Jeremy M.
AU - and Norton, Nadine
AU - Zhang, Nancy
AU - Hakonarson, Hakon
AU - Gao,
AU - Cynthia
AU - Citri, Ami
AU - Hansen, Mark
AU - Ripke, Stephan and
AU - Dudbridge, Frank
AU - Holmans, Peter A.
AU - Schizophrenia Psychiat GWAS
AU - Consor
JO - AMERICAN JOURNAL OF PSYCHIATRY
PY - 2012
VL - 169
TODO - 9
SP - 963-973
PB - AMER PSYCHIATRIC PUBLISHING, INC
SN - 0002-953X
TODO - 10.1176/appi.ajp.2012.11091423
TODO - null
TODO - Objective: The authors used a genome-wide association study (GWAS) of
multiply affected families to investigate the association of
schizophrenia to common single-nucleotide polymorphisms (SNPs) and rare
copy number variants (CNVs).
Method: The family sample included 2,461 individuals from 631 pedigrees
(581 in the primary European-ancestry analyses). Association was tested
for single SNPs and genetic pathways. Polygenic scores based on family
study results were used to predict case-control status in the
Schizophrenia Psychiatric GWAS Consortium (PGC) data set, and
consistency of direction of effect with the family study was determined
for top SNPs in the PGC GWAS analysis. Within-family segregation was
examined for schizophrenia-associated rare CNVs.
Results: No genome-wide significant associations were observed for
single SNPs or for pathways. PGC case and control subjects had
significantly different genome-wide polygenic scores (computed by
weighting their genotypes by log-odds ratios from the family study)
(best p=10(-17), explaining 0.4% of the variance). Family study and PGC
analyses had consistent directions for 37 of the 58 independent best PGC
SNPs (p=0.024). The overall frequency of CNVs in regions with reported
associations with schizophrenia (chromosomes 1q21.1, 15q13.3, 16p11.2,
and 22q11.2 and the neurexin-1 gene [NRXN1]) was similar to previous
case-cortrol studies. NRXN1 deletions and 16p11.2 duplications (both of
which were transmitted from parents) and 22q11.2 deletions (de novo in
four cases) did not segregate with schizophrenia in families.
Conclusions: Mary common SNPs are likely to contribute to schizophrenia
risk, with substantial overlap in genetic risk factors between multiply
affected families and cases in large case-control studies. Our findings
are consistent with a role for specific CNVs in disease pathogenesis,
but the partial segregation of some CNVs with schizophrenia suggests
that researcher; should exercise caution in using them for predictive
genetic testing until their effects in diverse populations have been
fully studied.
ER -