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Integrative analyses of major histocompatibility complex loci in the genome-wide association studies of major depressive disorder.

ABSTRACT: Recent European genome-wide association studies (GWAS) have revealed strong statistical correlations between MDD and numerous zero-to-high linked variants in the genomic region containing major histocompatibility complex (MHC) genes (MHC region), but the underlying biological mechanisms are still unclear. To better understand the roles of this genomic region in the neurobiology of MDD, we applied a convergent functional genomics approach to integrate GWAS data of MDD relevant biological phenotypes, gene-expression analyses results obtained from brain samples, and genetic analyses of independent Chinese MDD samples. We observed that independent MDD risk variants in the MHC region were also significantly associated with the relevant biological phenotypes in the predicted directions, including the emotional and cognitive-related phenotypes. Gene-expression analyses further revealed that mRNA expression levels of several MHC region genes in the human brain were associated with MDD risk SNPs and diagnostic status. For instance, a brain-enriched gene ZNF603P consistently showed lower mRNA levels in the individuals carrying MDD risk alleles and in MDD patients. Remarkably, we further found that independent MDD risk SNPs in the MHC region likely converged to affect the mRNA level(s) of the same gene(s), and Europeans and Han Chinese populations have a substantial shared genetic and molecular basis underlying MDD risk associations in the MHC region. These results highlighted several potential pivotal genes at the MHC region in the pathogenesis of MDD. Their common impacts on multiple psychiatric relevant phenotypes also implicated the neurological processes shared by different psychological processes, such as mood and/or cognition, shedding lights on their potential biological mechanisms.

SUBMITTER: Li H

PROVIDER: S-EPMC6785001 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Integrative analyses of major histocompatibility complex loci in the genome-wide association studies of major depressive disorder.

Li Huijuan H Chang Hong H Song Xueqin X Liu Weipeng W Li Lingyi L Wang Lu L Yang Yongfeng Y Zhang Luwen L Li Wenqiang W Zhang Yan Y Zhou Dong-Sheng DS Li Xingxing X Zhang Chen C Fang Yiru Y Sun Yan Y Dai Jia-Pei JP Luo Xiong-Jian XJ Yao Yong-Gang YG Xiao Xiao X Lv Luxian L Li Ming M

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20190216 9

Recent European genome-wide association studies (GWAS) have revealed strong statistical correlations between MDD and numerous zero-to-high linked variants in the genomic region containing major histocompatibility complex (MHC) genes (MHC region), but the underlying biological mechanisms are still unclear. To better understand the roles of this genomic region in the neurobiology of MDD, we applied a convergent functional genomics approach to integrate GWAS data of MDD relevant biological phenotyp ...[more]

PMID: 30771788

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Project description:Background: Major Depressive Disorder (MDD) is a moderately heritable disorder with a high lifetime prevalence. At present, laboratory blood tests to support MDD diagnosis are not available. Methods: We used a classifier approach on blood gene expression profiles of a unique set of non-medicated subjects (MDD patients and controls) to select genes of which expression is predictive for disease status. To reveal blood gene expression changes related to MDD disease, we applied a powerful ex vivo stimulus to the blood, i.e. incubation with lipopolysaccharide (LPS; 10 ng/ml blood). Results: Based on LPS-stimulated blood gene expression using whole-genome microarrays in 42 subjects (primary cohort; 21 MDD patients (mean age 42.3 years), 21 healthy controls (mean age 41.9 years)), we identified a set of genes (CAPRIN1, CLEC4A, KRT23, MLC1, PLSCR1, PROK2, ZBTB16) that serves as a molecular signature of MDD. These findings were validated for the primary cohort using an independent quantitative PCR method (P = 0.007). The difference between depressive patients and controls was confirmed (P = 0.019) in a replication cohort of 13 patients with MDD (mean age 42.8 years) and 14 controls (mean age 45.6 years). The MDD-signature score comprised of expression levels of 7 genes could discriminate depressive patients from controls with sensitivity of 76.9% and specificity of 71.8%. Conclusions: We show for the first time that molecular analysis of stimulated blood cells can be used as an endophenotype for MDD diagnosis, which is a milestone in establishing biomarkers for neuropsychiatric disorders with moderate heritability in general. Our results may provide a new entry point for following and predicting treatment outcome, as well as prediction of severity and recurrence of MDD. In total, 33 MDD patients and 34 healthy controls were analyzed using basal gene expression in whole blood, and gene expression from whole blood that was stimulated with LPS for 5-6 h, using microarrays. Patients were arbitrarily selected from all patients to serve as primary cohort (nMDD = 21 (MDD01-MDD21); nControls = 21 (Con01-Con21)), or replication cohort (nMDD = 12 (MDD22-MDD35); nControls = 13 (Con22-Con37)) using microarrays. This submission does not include Samples CON21_LPS or CON30_LPS.

Project description:Psoriasis is a common inflammatory skin disease characterized by thickened scaly red plaques. Previously we have performed a genome-wide association study (GWAS) on psoriasis with 1,359 cases and 1,400 controls, which were genotyped for 447,249 SNPs. The most significant finding was for SNP rs12191877, which is in tight linkage disequilibrium with HLA-Cw*0602, the consensus risk allele for psoriasis. However, it is not known whether there are other psoriasis loci within the MHC in addition to HLA-C. In the present study, we searched for additional susceptibility loci within the human leukocyte antigen (HLA) region through in-depth analyses of the GWAS data; then, we followed up our findings in an independent Han Chinese 1,139 psoriasis cases and 1,132 controls. Using the phased CEPH dataset as a reference, we imputed the HLA-Cw*0602 in all samples with high accuracy. The association of the imputed HLA-Cw*0602 dosage with disease was much stronger than that of the most significantly associated SNP, rs12191877. Adjusting for HLA-Cw*0602, there were two remaining association signals: one demonstrated by rs2073048 (p = 2 x 10(-6), OR = 0.66), located within c6orf10, a potential downstream effecter of TNF-alpha, and one indicated by rs13437088 (p = 9 x 10(-6), OR = 1.3), located 30 kb centromeric of HLA-B and 16 kb telomeric of MICA. When HLA-Cw*0602, rs2073048, and rs13437088 were all included in a logistic regression model, each of them was significantly associated with disease (p = 3 x 10(-47), 6 x 10(-8), and 3 x 10(-7), respectively). Both putative loci were also significantly associated in the Han Chinese samples after controlling for the imputed HLA-Cw*0602. A detailed analysis of HLA-B in both populations demonstrated that HLA-B*57 was associated with an increased risk of psoriasis and HLA-B*40 a decreased risk, independently of HLA-Cw*0602 and the C6orf10 locus, suggesting the potential pathogenic involvement of HLA-B. These results demonstrate that there are at least two additional loci within the MHC conferring risk of psoriasis.

Dataset Information

Integrative analyses of major histocompatibility complex loci in the genome-wide association studies of major depressive disorder.

Publications

Integrative analyses of major histocompatibility complex loci in the genome-wide association studies of major depressive disorder.

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