Genetics of schizophrenia: What do we know?
Researchers are discovering clues to predict susceptibility, improve treatment
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Genetic factors play a major role in the etiology and development of schizophrenia. Genetic linkage studies and twin studies have estimated the heritability of schizophrenia to be 70% to 90%.1 Research on the genetic underpinnings of schizophrenia has accelerated since the Human Genome Project was completed in 2001, which opened the door to expanding our understanding of molecular mechanisms of human diseases. Experts have hailed the dawn of personalized medicine,2 hoping that we will be able to use knowledge of the human genome to tailor individual treatment.
In this article we review some significant recent findings in genetics of schizophrenia. Gene names are italicized and proteins coded by genes are not. The names, functions, and locations of all genes included in this article appear in Table 1. For a glossary of genetic terms, see Table 2.
Select genes and their functions
Calcium channel, voltage-dependent, L type, alpha 1C subunit
Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization
Key enzyme in degradation of dopamine and norepinephrine
CUB and Sushi multiple domains 1
One of the proteins that modulate the classical complement pathway, part of the immune system
Cytochrome P450 2D6
Key enzyme in drug metabolism
Chromosome 10 open reading frame 26
Disrupted in schizophrenia 1
Neurite outgrowth, cortical development, synaptic function
Dopamine receptor D1
D1 receptors regulate neuronal growth and development, mediate behavioral responses, and modulate D2 receptor-mediated events
Dopamine receptor D2
D2 receptors regulate motor activities and information processing in the brain
Dystrobrevin binding protein 1
Neurodevelopment and synaptic transmission
Major histocompatibility complex, class II, DQ beta 1
Plays a central role in the immune system by presenting peptides derived from extracellular proteins
Serotonin receptor 2C
Modulate mood, food intake behavior, and feeling of satiety
Melanocortin 4 receptor
Modulate food intake behavior and feeling of satiety
Major histocompatibility complex
Immune function; neurodevelopment, synaptic plasticity
Post-transcriptional regulation of messenger RNAs; neuron maturation, adult neurogenesis
Key enzyme in folate metabolism
Transcription factor 4
Neuronal transcriptional factor, neurogenesis
Tryptophan hydroxylase 1
Key enzyme in biosynthesis of serotonin
Zinc finger protein 804A
Transcription factor, neuronal connectivity in the dorsolateral prefrontal cortex
Glossary of genetic terms
Allele: One of several variants of a gene, usually referring to a specific site within the gene
Association study: Genetic association refers to the association between a particular genotype and a phenotypic trait in the population. Genetic association studies aim to test whether single-locus alleles genotype frequencies or multi-locus haplotype frequencies differ between 2 groups (such as cases and controls)
Candidate gene study: A study that evaluates association of specific genetic variants with outcomes or traits of interest, selecting variants to be tested according to explicit considerations (known or postulated biology or function, previous studies, etc.)
Case-control design: An association study design in which the primary comparison is between a group of individuals (cases) ascertained for the phenotype of interest (eg, patients with schizophrenia) and a second group (control) ascertained for not having the phenotype (eg, healthy controls)
Copy number variation: A class of DNA sequence variant (including deletions and duplications) in which the result is a departure from the expected 2-copy representation of DNA sequence (ie, each person has 2 copies of the same chromosome)
Endophenotype: Phenotypes that are genetically determined, directly measurable traits as part of a complex illness. This term is used to connect the pathway from genes to a disease (eg, impairment in working memory is an endophenotype of schizophrenia)
Genetic association: A relationship that is defined by the nonrandom occurrence of a genetic marker with a trait, which suggests an association between the genetic marker (or a marker close to it) and disease pathogenesis
Genetic marker: A specific genetic variant known to be associated with a recognizable trait or disease
Genome: The entire collection of genetic information (or genes) that an organism possesses
Genome-wide association study: A study that evaluates association of genetic variation with outcomes or traits of interest by using 300,000 to 1,000,000 markers across the whole genome. No hypothesis about any particular gene is required for GWAS
Genotype: The genetic constitution of an individual, either overall or at a specific gene
Heritability (h2): A measure of the strength of genetic effects on a trait. It is defined as the proportion of the phenotypic variation in a trait that is attributable to genetic effects
Linkage disequilibrium (LD): Two polymorphic loci are in LD when they are co-located, and alleles at those loci are distributed non-randomly with respect to each other on chromosomes in the population
Linkage study: A technique used in genetic epidemiology that focuses on linking a chromosome region to transmission of a particular trait across multiple familial generations
Phenotype: The observable characteristics of a cell or organism, usually being the results of the product coded by a gene (genotype)
Polymorphism: The existence of ≥2 variants of a gene, occurring in a population, with at least 1% frequency of the less common variant
Recombination hotspot: Recombination is breaking and rejoining of DNA strands to form new DNA molecules encoding a novel set of genetic information. Recombination hotspots are individual regions within the genome that have frequent recombination events (eg, the human leukocyte antigen region is a recombination hotspot)
Single nucleotide polymorphism: A single base pair change in the DNA sequence at a particular point, compared with the “common” or “wild type” sequence
Translocation: A type of chromosomal abnormality resulted by rearrangement of parts between nonhomologous chromosomes, often leading to cancer or developmental abnormalities
Focusing on single nucleotide polymorphisms
Genetic research of diseases previously relied on linkage studies, which focus on linking a chromosome region to transmission of a particular trait across multiple familial generations. This approach has identified several genomic regions that may be associated with schizophrenia, but most of these regions contain multiple genes and are not specific to schizophrenia.
Today, many genetic studies examine variations of a single nucleotide in the DNA sequence, ie, a change of 1 letter in a particular location on the DNA chain. Single nucleotide polymorphisms (SNPs)—relatively common DNA variations found in >5% of the population—have been a major focus of psychiatric genetics in the past decade. Technology now allows researchers to simultaneously genotype millions of SNPs across the genome, producing tremendous power to investigate the entire genome in relation to a phenotype (a disease or a trait) in genome-wide association studies (GWAS).3 GWAS do not require an a priori hypothesis regarding which regions or genes may be important, and have yielded many novel genetic variants implicated in schizophrenia.
Genetic researchers initially hoped to find that one or a few genes are responsible for schizophrenia. However, recent research revealed that many genes may be involved in susceptibility to schizophrenia, and that a particular gene may contribute to the risk of not only schizophrenia but also other psychiatric disorders such as bipolar disorder (BD).
Discovery of the DISC1 gene is an example of how our understanding of the complex genetic architecture in psychiatric disorders has evolved. In 2000, a linkage study in a Scottish family cohort found a translocation on chromosome 1, t(1:11), highly correlated with schizophrenia.4 Later studies found that this translocation directly disrupts a gene, which researchers named “disrupted in schizophrenia 1.” The protein encoded by DISC1 appears to provide a scaffold to other proteins involved in multiple cellular functions, particularly regulation of brain development and maturation. It is involved in neuronal proliferation, differentiation, and migration via various signaling pathways by interacting with many other proteins.5 Disruption of DISC1 results in dysfunction in multiple neurodevelopmental processes, significantly increasing susceptibility not only for schizophrenia but also for BD and depression.
Many common variants of DISC1 slightly alter expression levels of the gene, which may exert subtle but pervasive effects on neural circuitry development. DISC1 knockout mouse models showed close interactions between DISC1 and N-methyl-d-aspartate receptors and dopamine D2 receptors, linking to the glutamate hypothesis of schizophrenia and the common site of action of antipsychotics. Despite advances in understanding the biology of DISC1, large case-control studies have not found a consistent association between DISC1 and schizophrenia.6,7 It is possible that DISC1 pathology represents one subtype of schizophrenia that is not prevalent among the general population; therefore, large-scale epidemiologic studies could not find evidence to support DISC1’s role in schizophrenia.
DTNBP1 is another schizophrenia susceptibility gene discovered in linkage studies. Originally found in a large Irish cohort, several SNPs of DTNBP1 were significantly associated with schizophrenia.8 A meta-analysis of candidate genes identified DTNBP1 as one of 4 genes with the strongest evidence for association with schizophrenia (the other 3 are DRD1, MTHFR, and TPH1).9 DTNBP1 is widely expressed in the brain and is present in presynaptic, postsynaptic, and microtubule locations implicated in a number of brain functions, including synaptic transmission and neurite outgrowth in a developing organism. Furthermore, DTNBP1 is associated with cognitive functions in schizophrenia patients10 as well as in control subjects.11 Cognitive impairment is considered an endophenotype for schizophrenia. Similar to DISC1 and other candidate genes, DTNBP1 has not emerged as a significant hit in later, large-scale GWAS studies.
Since the first schizophrenia GWAS in 2007,12 >15 GWAS have been published, with increasingly larger samples sizes. GWAS are based on the “common disease/common variant hypothesis” that common disorders such as diabetes, macular degeneration, and schizophrenia are caused by multiple common variants in the genome. Because GWAS can analyze hundreds of thousands of SNPs simultaneously, a stringent criterion (usually P < 5×10-8) is used to gauge statistical significance to correct for multiple testing. Because most effect sizes associated with genetic markers in psychiatry are fairly small (odds ratios [ORs] are approximately 1.1 to 1.2), large samples are required to detect significant effects. Several international consortia have accumulated large samples. The Psychiatric GWAS Consortium has >17,000 patients with schizophrenia, >11,000 with BD, >16,000 with major depression, and >50,000 healthy controls. This wave of GWAS has implicated several novel genomic regions in schizophrenia pathophysiology, including ZNF804A, the major histocompatibility complex (MHC) region, and MIR137.
ZNF804A was the first gene that reached genome-wide significance in a large GWAS,13 and this finding has been replicated. The function of this novel gene largely is unknown. ZNF804A is widely expressed in the brain, especially in the developing hippocampus and the cortex as well as in the adult cerebellum. Recent studies found that ZNF804A is a putative transcription factor, upregulating expression of catechol-O-methyltransferase while downregulating dopamine D2 receptors in animal studies.14 The minor allele of SNP rs1344706 was associated with impaired brain functional connectivity in a human study.15 More work is needed to understand how this gene increases schizophrenia susceptibility.
The MHC region on chromosome 6p22.1,1 also was significant in schizophrenia GWAS,16,17 and this may be the most replicated schizophrenia GWAS finding. This region is a recombination hotspot and harbors many genetic variants. Many immune-related genes previously were associated with autoimmune and infectious disorders, which may suggest that the immunologic system plays a role in schizophrenia pathogenesis. These genes also may involve neurodevelopment, synaptic plasticity, and other neuronal processes.18 However, the complex gene composition in the region makes it difficult to pinpoint the exact signal to schizophrenia pathophysiology.
The most recent finding from the largest GWAS is MIR137,19 coding for microRNA 137, which was associated with schizophrenia at P=1.6×10-11 in 17,836 patients and 33,859 controls. MicroRNAs are small, noncoding RNA fragments that are involved in post-transcriptional regulation of messenger RNAs. MIR137 plays important roles in neuron maturation and adult neurogenesis by acting at the level of dendritic morphogenesis and spine development.20 More interestingly, the other 4 loci achieving genome-wide significance in the same GWAS (TCF4, CACNA1C, CSMD1, and C10orf26) contain predicted target sites of MIR137. This suggests MIR137-mediated dysregulation may be an etiologic mechanism in schizophrenia.
Limitations of these findings. The effect sizes of these genetic variants are small, explaining only 1% to 2% of genetic risks of schizophrenia. However, this is not unique to schizophrenia or psychiatry. “Missing heritability” is puzzling in other branches of medicine.21 Future research will focus on gene-environment interactions as well as gene-gene interactions in relation to schizophrenia’s neurodevelopmental processes.