Περίληψη:
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.
Συγγραφείς:
Levinson, Douglas F.
Shi, Jianxin
Wang, Kai
Oh, Sang and
Riley, Brien
Pulver, Ann E.
Wildenauer, Dieter B.
Laurent,
Claudine
Mowry, Bryan J.
Gejman, Pablo V.
Owen, Michael J.
and Kendler, Kenneth S.
Nestadt, Gerald
Schwab, Sibylle G. and
Mallet, Jacques
Nertney, Deborah
Sanders, Alan R.
Williams,
Nigel M.
Wormley, Brandon
Lasseter, Virginia K.
Albus,
Margot
Godard-Bauche, Stephanie
Alexander, Madeline
Duan,
Jubao
O'Donovan, Michael C.
Walsh, Dermot
O'Neill, Anthony
and Papadimitriou, George N.
Dikeos, Dimitris
Maier, Wolfgang
and Lerer, Bernard
Campion, Dominique
Cohen, David
Jay,
Maurice
Fanous, Ayman
Eichhammer, Peter
Silverman, Jeremy M.
and Norton, Nadine
Zhang, Nancy
Hakonarson, Hakon
Gao,
Cynthia
Citri, Ami
Hansen, Mark
Ripke, Stephan and
Dudbridge, Frank
Holmans, Peter A.
Schizophrenia Psychiat GWAS
Consor
