Is the roller coaster ride in schizophrenia genetics coming to an end? Breakthrough or wishful thinking?

Family, twin and adoption studies demonstrate evidence for a strong genetic component in the aetiology of schizophrenia. The relative contribution of genetic factors to the aetiology of schizophrenia has been estimated to be approximately 80%. The mode of inheritance is complex and non-Mendelian, involving the combined action of several genes (Maier et al. 2005; Owen 2005; Weinberger 2005). The risk of developing the disease increases exponentially with the genetic relatedness to an individual suffering from the disorder. Third-degree relatives carry an approximate 2% chance of developing schizophrenia in comparison with the 1% risk for schizophrenia in the general population, and the risk increases to 9% in first-degree relatives. Moreover, in monozygotic (MZ) twins, the concordance rate is approximately 50%. Adoption studies provide strong evidence that the familial aggregation is not the result of shared environmental factors, as individuals adopted into families containing an affected individual do not have an increased risk of developing schizophrenia, whereas the existence of a biological relative with schizophrenia does lead to an increased risk in adoptees.

For schizophrenia, the number of susceptibility loci, the attributable risk conferred by each locus, and the degree of interaction between loci remain unknown. Two main approaches have been generally used in the search for susceptibility genes: linkage studies, which do not have to rely on specific biological hypotheses, seek to identify chromosomal regions containing susceptibility loci; and association studies, which are sensitive enough to detect small gene effects, but have to rely on plausible candidate genes (Norton et al. 2006; Owen et al. 2007). Results from these studies have been summarized in excellent reviews and only an overview is given.

Linkage studies are based on the fact that genetic variants located closely one to the other are more likely to be inherited together than genetic variants located further apart. First linkage studies in schizophrenia were driven by the assumption that genes of major effect can be identified, similar to the highly successful detection of genes with major effects in monogenic diseases. However, early positive findings were not replicated (Detera-Wadleigh et al. 1989; Sherrington et al. 1998), suggesting that highly penetrant mutations are rare (McGuffin et al. 1996). Nevertheless, moderately significant evidence for linkage has been found in more than one data set in several, unfortunately rather broad (often >20–30 cM) chromosomal regions: 5q21–q31, 6p24–p22, 6q, 8p22–p21, 10p15–p11, 13q14.1–q32, and 22q11–q12 (Lin et al. 1995; Gill et al. 1996; Schizophrenia Linkage Collaborative Group 1996; Blouin et al. 1998; Faraone et al. 1998; Schwab et al. 1997, 2003; Straub et al. 1997, 1998, 2002; Levinson 2000; Brzustowicz et al. 2000). The largest meta-analysis on linkage studies to date suggests several candidate chromosomal regions (1p13.3–q23.3; 2p12–q22.1; 2q22.1–q23.3; 3p25.3–p22.1; 5q23.2–q34; 6p–p22.3; 6p22.3–p21.1; 8p22–p21.1; 11q22.3–q24.1; 22p–q12.3) for schizophrenia (Lewis et al. 2003). Thus, there is evidence implicating a number of chromosomal regions, which is consistent with the existence of multiple susceptibility genes of weak to moderate effect. Unfortunately, the methodology of linkage studies does not allow detecting the actual susceptibility genes of limited effect size, since the number of families required to localize these genes make these studies virtually impracticable.

Genetic association studies provide an alternative and powerful approach of identifying such genes in feasible sample sizes. These studies examine if genetic variants are associated with a certain trait or disorder. The simplest design compares the frequencies of genetic variants between groups of non-related cases and controls. Unfortunately, these studies have to rely on candidate genes derived from neurobiological research. Given that the pathophysiology of schizophrenia is far from being understood, genetic association studies had only limited success so far (Sanders et al. 2008).

Currently a new, hypothesis-free approach has arisen due to the new technical possibilities in genotyping. The identification of genetic vulnerability factors should involve a comprehensive survey of the entire human genome. Developing tools such as high-density genetic maps for genome-wide association analyses has been the most important recent goal of the Human Genome Project. Recent progress in the field of parallel single nucleotide polymorphisms (SNPs) typing has made SNP-based genome screens an option. Recent genome-wide association studies have provided proof of principle and yielded several genes showing a strong association with complex diseases or traits (Carrasquillo et al. 2002; Goertsches et al. 2003; Jonasdottir et al. 2003; Jagiello et al. 2004). The first GWA study on schizophrenia with more than 500,000 SNPs was performed by Lencz et al. (2007) and showed association of CSF2RA (colony stimulating factor, receptor 2α). Further GWA studies on schizophrenia are under way and further replication studies will show if these genes are new putative genes for schizophrenia.

There is a long-lasting assumption in psychiatric genetics that common genetic variants with small effects are enhancing the risk to develop schizophrenia. Although debated for some time, the other side of the coin, namely that rare genetic variations with large effects may account for a significant number of schizophrenia cases, has been somehow neglected. However, rare genetic variants with large effects on schizophrenia are known for a long time. One represents a private translocation in a Scottish family which disrupts DISC1. A more common deletion of chromosome 22q11 has also been repeatedly reported to substantially enhance the risk for developing schizophrenia. Structural chromosomal abnormalities are emerging as an important genomic cause of neuropsychiatric diseases, including mental retardation, autism and more recently schizophrenia. In a paper published in Science, Walsh et al. (2008) investigated individuals with schizophrenia and controls in order to identify microdeletions and microduplications larger than 100,000 base pairs. Novel deletions and duplications of genes were present in 5% of controls versus 15% of cases and 20% of young onset cases. These mutations in schizophrenia cases disrupted genes disproportionately from signalling networks controlling neurodevelopment, including neuregulin and glutamate pathways. The authors argue that these results suggest that multiple, individually rare mutations altering genes in neurodevelopmental pathways contribute to schizophrenia. Did this study investigate only the tip of an ice berg? Are a substantial number of schizophrenia cases caused by more or less rare copy number variations? It is also interesting that some of the genes may show association not only to schizophrenia but also to mental retardation and autism, an example is neurexin 1. Are we going to define a number of new diseases at the interface between mental retardation, autism and schizophrenia? There is new hope that these new avenues will help in understanding the neurobiology of schizophrenia in more depth, leading to the development of new innovative diagnostic tools and therapies as was the case after the discovery of rare APP and presenilin 1 and 2 mutations in Alzheimer's disease.