TY - JOUR
T1 - Fine Mapping on Chromosome 10q22-q23 Implicates Neuregulin 3 in Schizophrenia
AU - Chen, Pei Lung
AU - Avramopoulos, Dimitrios
AU - Lasseter, Virginia K.
AU - McGrath, John A.
AU - Fallin, M. Daniele
AU - Liang, Kung Yee
AU - Nestadt, Gerald
AU - Feng, Ningping
AU - Steel, Gary
AU - Cutting, Andrew S.
AU - Wolyniec, Paula
AU - Pulver, Ann E.
AU - Valle, David
N1 - Funding Information:
We are indebted to all the patients and controls for participation in this research. Genotyping services were provided by the Johns Hopkins Center for Inherited Disease Research (CIDR). CIDR is fully funded through a federal contract from the National Institutes of Health to The Johns Hopkins University, contract number NO1-HG-65403. This study was funded by National Institutes of Mental Health grant RO1MH057314 and RO1MH068406, and by the Wasie Foundation (A.E.P.). This project also was funded in part by the National Alliance for Research on Schizophrenia and Depression (D.V. and D.A.). None of the authors have any conflict of interest concerning this manuscript. We also thank Sandy Muscelli for assistance with the manuscript.
Copyright:
Copyright 2009 Elsevier B.V., All rights reserved.
PY - 2009/1/9
Y1 - 2009/1/9
N2 - Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 × 10-5), we performed a peakwide association fine mapping study by using 1414 SNPs across ∼12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 × 10-7. We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 × 10-2), with a combined p value of 2.30 × 10-7. After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 × 10-3. NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.
AB - Linkage studies have implicated 10q22-q23 as a schizophrenia (SZ) susceptibility locus in Ashkenazi Jewish (AJ) and Han Chinese from Taiwan populations. To further explore our previous linkage signal in the AJ population (NPL score: 4.27, empirical p = 2 × 10-5), we performed a peakwide association fine mapping study by using 1414 SNPs across ∼12.5 Mb in 10q22-q23. We genotyped 1515 AJ individuals, including 285 parent-child trios, 173 unrelated cases, and 487 unrelated controls. We analyzed the binary diagnostic phenotype of SZ and 9 heritable quantitative traits derived from a principal components factor analysis of 73 items from our consensus diagnostic ratings and direct assessment interviews. Although no marker withstood multiple test correction for association with the binary SZ phenotype, we found strong evidence of association by using the "delusion" factor as the quantitative trait at three SNPs (rs10883866, rs10748842, and rs6584400) located in a 13 kb interval in intron 1 of Neuregulin 3 (NRG3). Our best p value from family-based association analysis was 7.26 × 10-7. We replicated this association in the collection of 173 unrelated AJ cases (p = 1.55 × 10-2), with a combined p value of 2.30 × 10-7. After performing 10,000 permutations of each of the phenotypes, we estimated the empirical study-wide significance across all 9 factors (90,000 permutations) to be p = 2.7 × 10-3. NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. These biological properties together with our linkage and association results strongly support NRG3 as a gene involved in SZ.
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U2 - 10.1016/j.ajhg.2008.12.005
DO - 10.1016/j.ajhg.2008.12.005
M3 - Article
C2 - 19118813
AN - SCOPUS:58049209657
VL - 84
SP - 21
EP - 34
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 1
ER -