Schizophrenia is a mental illness that causes the patient to have difficulty separating what is real from what is not. The web page wikipedia:schizophrenia is a good place to learn about the disease.
A 2016 schizophrenia study focusing on the MHC region, which in population studies has shown the strongest genetic association of any chromosomal region to schizophrenia, teased apart three independent sources of the association. One signal, best represented by rs13194504, came from the distal end of the region. A second signal, perhaps best represented by rs210133, came from the proximal end. In between these two came the signal leading to the major finding of this publication: structural alleles of the C4A and C4B genes lead to different amounts of C4A expression, and the higher the expression of C4A, the higher the risk of schizophrenia. [The maximum relative risk observed was 1.27.] As stated by the authors, "These results implicate excessive complement activity (i.e. "synapse pruning") in the development of schizophrenia and may help explain the reduced numbers of synapses in the brains of individuals with schizophrenia."[PMID 26814963]
A 2015 study analyzing over 22,000 schizophrenia patient samples by a new multicomponent, multi-trait variance-components analysis methodology concluded that there could be 20,000 causal SNPs for schizophrenia, each with a quite small effect. If true, this extremely high number of genetic variants is far greater than the numbers predicted for other common diseases, and the authors conclude that genetic testing for schizophrenia will not be simple.[PMID 26523775]
A 2014 very large genome-wide association study identified 108 common SNPs as possibly associated with schizophrenia, 83 of which are newly identified in this study. It is expected that ultimately over 170 loci will be validated from this study. [PMID 25056061] Biological insights from 108 schizophrenia-associated genetic loci. This GWAS included 36,989 cases and 113,075 controls. R2 (a measure of variance in case-control status explained) is now increased from 0.03 (from a 2009 GWAS study) to 0.184.
A 2013 genome-wide association study provided evidence that many independent, mostly common SNPs (~6,300-10,200) can collectively account for at least 32% of the variance in the liability to schizophrenia [PMID 23974872], indicating that large, highly-powered GWA studies assaying common variants can be useful for gaining information about the genetic roots of the disease. The study first independently compared 9,871,789 SNPs between 5001 schizophrenia cases and 6,243 controls from the Swedish population. They then followed with a meta-analysis with previous schizophrenia GWAS samples (8,832 cases and 19,762 controls). Finally, they tested SNPs in 168 genomic regions of interest in another large set of independent samples (7,413 schizophrenia cases, 19,762 controls, and 581 parent-offspring trios, where the child has schizophrenia and both parents are unaffected).
Using this large data set, they identified 24 SNPs in 22 separate genomic loci as associated with schizophrenia at the genome-wide level. Thirteen of these loci had not previously been associated with schizophrenia and eight replicated previous GWAS findings. The authors highlight three major themes from their results. 1) Significant SNPs were found in genes encoding calcium channels, including rs1006737 and rs17691888. 2) The strongest SNP association with schizophrenia in the study was rs114002140 in the extended major histocompatibility complex (MHC), as previously reported to be associated with the disease [PMID 19571811], [PMID 19571809], [PMID 19571808], [PMID 21926974] 3) Several lines of evidence support a potential role for MIR137 in schizophrenia etiology and the authors found a common variant, rs1198588, upstream of MIR137 to be associated with schizophrenia. Several of the genes predicted to be located in the 22 significantly associated genomic loci in this study have predicted target sites for miR-137.
The SNPs that were associated with schizophrenia in this study (and the reported risk allele frequency in controls, combined odds ratio reported, and if the association with the linked genetic loci is novel or has replicated a previous finding):
- rs114002140, AG, frequency = 0.763, odds ratio = 1.167, replicated association [PMID 19571811], [PMID 19571809], [PMID 19571808], [PMID 21926974]
- rs7085104, AG, frequency = 0.645, odds ratio = 1.110, replicated association
- rs6461049, TC, frequency – 0.571, odds ratio = 1.107, novel association
- rs1198588, AT, frequency = 0.214, odds ratio = 0.889, replicated association
- rs1006737, AG, frequency = 0.332, odds ratio = 1.103, replicated association [PMID 21926974], [PMID 1926972], [PMID 18711365]
- rs17691888, AG, frequency = 0.114, odds ratio = 0.862, replicated association [PMID 23453885]
- rs4129585, AC, frequency = 0.439, odds ratio = 1.091, novel association
- rs10789369, AG, frequency = 0.383, odds ratio = 1.095, novel association
- rs7940866, AT, frequency = 0.513, odds ratio = 0.921, novel association
- rs17504622, TC, frequency = 0.050, odds ratio = 1.238, novel association
- rs2905424, TC, frequency = 0.348, odds ratio = 1.092, novel association
- rs2373000, TC, frequency = 0.402, odds ratio = 1.087, novel association
- rs6878284, TC, frequency = 0.637, odds ratio = 0.920, novel association
- rs4687552, TC, frequency = 0.641, odds ratio = 1.086, replicated association
- rs12991836, AC, frequency = 0.652, odds ratio = 0.922, novel association
- rs2949006, TG, frequency = 0.192, odds ratio = 1.102, novel association
- rs4801131, TC, frequency = 0.926, odds ratio = 0.925, novel association
- rs778371, AG, frequency = 0.719, odds ratio = 0.920, novel association
- rs14403, TC, frequency = 0.227, odds ratio = 0.910, novel association
- rs11532322, AG frequency = 0.318, odds ratio = 1.094, novel association
- rs1538774, CG, frequency = 0.260, odds ratio = 0.917, replicated association
- rs11995572, TG, frequency = 0.135, odds ratio = 1.120, replicated association
- rs171748, AG, frequency = 0.471, odds ratio = 1.078, novel association
- rs2910032, TC, frequency = 0.531, odds ratio = 0.925, novel association
Mother vs child genetics affects the risk of schizophrenia. [1]
[2] Schizophrenia is widely held to stem from the combined effects of multiple common polymorphisms, each with a small impact on disease risk. We suggest an alternative view: that schizophrenia is highly heterogeneous genetically and that many predisposing mutations are highly penetrant and individually rare, even specific to single cases or families. This "common disease - rare alleles" hypothesis is supported by recent findings in human genomics and by allelic and locus heterogeneity for other complex traits.
Numerous SNPs have been linked to schizophrenia:
- rs10790212
- rs11743803 in the ACSL6 gene
- rs175174 in the ZDHHC8 gene; possibly not related to schizophrenia
- rs947267 in the DAOA gene
- rs27388 in the MEGF10 gene
- rs2270641 in the SLC18A1 gene
- rs17101921 on ch 10q25-26
- rs833497 in the DYM gene
- The SREBF1 and SREBF2 genes, which are involved in lipid metabolism, have been implicated in type-2 diabetes [PMID 18192539], Parkinson's disease [PMID 21738487]], and schizophrenia [PMID 18936756].
A (2007) whole genome association study identified several SNPs as significantly associated with schizophrenia, all located in the pseudoautosomal region of the X and Y chromosomes (Xp22.32/Yp11.3) [PMID 17522711]:
- rs4129148 near the CSF2RA gene
- rs28694718 and rs28414810, part of a haplotype block in intron 8 of the CSF2RA gene
- rs6422441, rs6603272, and rs17883192, all part of a haplotype block spanning introns 4, 5 and 6 of the IL3RA gene
Several meta-analyses have implicated one or more SNPs in the dopamine D2 receptor DRD2 gene as a risk factor, such as:
Another form of genetic variation is known as "runs of homozygosity" (ROH), whereby for relatively long stretches of a person's genome both chromosomes are identical. Nine specific regions have tentatively been found [PMID 18077426] to show ROHs to a greater degree in schizophrenics; the core SNPs from each of these regions are:
- rs11225703, on chromosome 11
- rs2848745, on chromosome 18
- rs17651507, on chromosome 17
- rs2437896, on chromosome 2
- rs2499846, on chromosome 1
- rs4958803, on chromosome 5
- rs2053149, on chromosome 14
- rs7582658, on chromosome 2
- rs2119783, on chromosome 8
Another theory attributes schizophrenia to an accumulation of multiple, individually rare mutations (i.e. not common SNPs) that alter genes in neurodevelopmental pathways. This was primarily based on a study of microdeletions and microduplications of size >100 kb that were identified by microarray comparative genomic hybridization of genomic DNA from 150 individuals with schizophrenia.[PMID 18369103]
There have also been numerous studies finding no statistically valid association between any single SNP and schizophrenia. For example: in a large genetic association study of 14 schizophrenia candidate genes (RGS4, DISC1, DTNBP1, STX7, TAAR6, PPP3CC, NRG1, DRD2, HTR2A, DAOA, AKT1, CHRNA7, COMT, and ARVCF) and 1,870 Caucasian patients, no SNPs were found to be statistically meaningful, and even the four functional polymorphisms in COMT, DRD2, and HTR2A showed no association. This study did not rule over small effects from these SNPs however.[PMID 18198266]
Some SNPs have also been reported to be associated with better treatment outcome:
- rs6280, correlated to better response to olanzapine
thinkgene Copy number variants (CNVs) at 22q11.2 may account for 15% of sporadic cases.
