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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.
Table 1
Select genes and their functions
| Gene | Name | Location | Function(s) |
|---|---|---|---|
| CACNA1C | Calcium channel, voltage-dependent, L type, alpha 1C subunit | 12p13.3 | Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization |
| COMT | Catechol-O-methyltransferase | 22q11.21 | Key enzyme in degradation of dopamine and norepinephrine |
| CSMD1 | CUB and Sushi multiple domains 1 | 8p23.2 | One of the proteins that modulate the classical complement pathway, part of the immune system |
| CYP2D6 | Cytochrome P450 2D6 | 22q13.1 | Key enzyme in drug metabolism |
| C10orf26 | Chromosome 10 open reading frame 26 | 10q24.32 | Unknown |
| DISC1 | Disrupted in schizophrenia 1 | 1q42 | Neurite outgrowth, cortical development, synaptic function |
| DRD1 | Dopamine receptor D1 | 5q35.1 | D1 receptors regulate neuronal growth and development, mediate behavioral responses, and modulate D2 receptor-mediated events |
| DRD2 | Dopamine receptor D2 | 11q23 | D2 receptors regulate motor activities and information processing in the brain |
| DTNBP1 | Dystrobrevin binding protein 1 | 6p22 | Neurodevelopment and synaptic transmission |
| HLA-DQB1 | Major histocompatibility complex, class II, DQ beta 1 | 6p21.3 | Plays a central role in the immune system by presenting peptides derived from extracellular proteins |
| HTR2C | Serotonin receptor 2C | Xq24 | Modulate mood, food intake behavior, and feeling of satiety |
| MC4R | Melanocortin 4 receptor | 18q22 | Modulate food intake behavior and feeling of satiety |
| MHC region | Major histocompatibility complex | 6p21-22 | Immune function; neurodevelopment, synaptic plasticity |
| MIR137 | MicroRNA 137 | 1p23.3 | Post-transcriptional regulation of messenger RNAs; neuron maturation, adult neurogenesis |
| MTHFR | Methylenetetrahydrofolate reductase | 1p36.3 | Key enzyme in folate metabolism |
| TCF4 | Transcription factor 4 | 18q21.2 | Neuronal transcriptional factor, neurogenesis |
| TPH1 | Tryptophan hydroxylase 1 | 11p15.3 | Key enzyme in biosynthesis of serotonin |
| ZNF804A | Zinc finger protein 804A | 2q32.1 | Transcription factor, neuronal connectivity in the dorsolateral prefrontal cortex |
Table 2
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 |