TY - JOUR
T1 - A multimodal attempt to follow-up linkage regions using RNA expression, SNPs and CpG methylation in schizophrenia and bipolar disorder kindreds
AU - Chagnon, Yvon C.
AU - Maziade, Michel
AU - Paccalet, Thomas
AU - Croteau, Jordie
AU - Fournier, Alain
AU - Roy, Marc André
AU - Bureau, Alexandre
N1 - Funding Information:
Funding This work was supported by the Canadian Institutes of Health research (CIHR, grants MOP-74430, MOP-119408 and MOP-114988) and by a Canada Research Chair (# 950–200810) in the genetics of neuropsychiatric disorders of which M. Maziade was the Chair. The data management system was supported by the Canada Foundation for Innovation Leadership Opportunity Fund (grant 27592).
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to European Society of Human Genetics.
PY - 2020/4/1
Y1 - 2020/4/1
N2 - The complexity of schizophrenia (SZ) and bipolar disorder (BD) has slowed down progress in understanding their genetic roots. Alternative genomic approaches are needed to bypass these difficulties. We attempted a multimodal approach to follow-up on reported linkage findings in SZ and BD from the Eastern Quebec kindreds in chromosomes 3q21, 4p34, 6p22, 8p21, 8p11, 13q11-q14, 15q13, 16p12, and 18q21. First, in 498 subjects, we measured RNA expression (47 K Illumina chips) in SZ and BD patients that we compared with their non-affected relatives (NARs) to identify, for each chromosomal region, genes showing the most significant differences in expression. Second, we performed SNP genotyping (700 K Illumina chips) and cis-eQTN analysis. Third, we measured DNA methylation on genes with RNA expression differences or eQTNs. We found a significant overexpression of the gene ITGB5 at 3q25 in SZ and BD after multiple testing p value adjustment. SPCS3 gene at 4q34, and FZD3 gene at 8p21, contained significant eQTNs after multiple testing corrections, while ITGB5 provided suggestive results. Methylation in associated genes did not explain the expression differences between patients and NARs. Our multimodal approach involving RNA expression, dense SNP genotyping and eQTN analyses, restricted to chromosomal regions having shown linkage, lowered the multiple testing burden and allowed for a deeper examination of candidate genes in SZ or BD.
AB - The complexity of schizophrenia (SZ) and bipolar disorder (BD) has slowed down progress in understanding their genetic roots. Alternative genomic approaches are needed to bypass these difficulties. We attempted a multimodal approach to follow-up on reported linkage findings in SZ and BD from the Eastern Quebec kindreds in chromosomes 3q21, 4p34, 6p22, 8p21, 8p11, 13q11-q14, 15q13, 16p12, and 18q21. First, in 498 subjects, we measured RNA expression (47 K Illumina chips) in SZ and BD patients that we compared with their non-affected relatives (NARs) to identify, for each chromosomal region, genes showing the most significant differences in expression. Second, we performed SNP genotyping (700 K Illumina chips) and cis-eQTN analysis. Third, we measured DNA methylation on genes with RNA expression differences or eQTNs. We found a significant overexpression of the gene ITGB5 at 3q25 in SZ and BD after multiple testing p value adjustment. SPCS3 gene at 4q34, and FZD3 gene at 8p21, contained significant eQTNs after multiple testing corrections, while ITGB5 provided suggestive results. Methylation in associated genes did not explain the expression differences between patients and NARs. Our multimodal approach involving RNA expression, dense SNP genotyping and eQTN analyses, restricted to chromosomal regions having shown linkage, lowered the multiple testing burden and allowed for a deeper examination of candidate genes in SZ or BD.
UR - http://www.scopus.com/inward/record.url?scp=85074825125&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074825125&partnerID=8YFLogxK
U2 - 10.1038/s41431-019-0526-y
DO - 10.1038/s41431-019-0526-y
M3 - Article
C2 - 31695175
AN - SCOPUS:85074825125
SN - 1018-4813
VL - 28
SP - 499
EP - 507
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 4
ER -