Spotlight: Unraveling the genetics
of schizophrenia
Misunderstanding abounds with schizophrenia, beginning with its name. The word “schizophrenia” is of Greek derivation and translates roughly as “split mind.” Despite this derivation, schizophrenia is neither similar nor related to multiple personality disorder, yet the two illnesses are frequently confused.
It is surprising for many to learn that schizophrenia is a common disease: some estimates predict that as much as 1% of the global population is affected. The illness typically surfaces during adolescence or early adulthood, a cruel interruption to lives in their prime. Hallucinations, delusions and paranoia conspire with the brain to disconnect sufferers from reality. Disorganized speech, thoughts and behavior emerge, as do emotional detachment and apathy, which eventually lead to social withdrawal. Those with schizophrenia grapple with a disease that typically renders them unable to function at work and in the community, and that also strains relationships with friends and family. Although treatment is successful for some, for most the course is one with relapses and only partial remission. Unfortunately, we do not understand the most basic aspects of the illness, such as what happens in the brain to trigger the disease.
Like patients with other mental illnesses, individuals with schizophrenia are stigmatized and often unfairly judged by society. They are frequently stereotyped as dangerous, violent and unpredictable, and somehow responsible for their disease. Personal accountability, however, is no greater than in diseases of the flesh, like cancer or diabetes. Conclusive evidence indicates that schizophrenia’s heritability — the level to which genes dictate disease — is quite high. Actually, it is higher than the heritabilities of several other common diseases, including breast cancer, heart disease in men and type II diabetes.
The myths and misinterpretations that surround schizophrenia, and the lack of understanding of its underlying biology, motivate me to help lift its shadowy cloak and shed light on its genetic components. Thankfully, others accompany me, including my colleagues in Pamela Sklar’s laboratory in the ӳý’s Neuropsychiatric Genetics group and in the Center for Human Genetic Research at MGH, where I am also an Instructor in Psychiatry, as well as our collaborators in the ӳý’s Psychiatric Disease Initiative and other researchers across the world. Two years ago, Sklar and our coworkers examined DNA from families in the Portuguese Islands with a history of schizophrenia. Studying such geographically isolated populations allowed us to pinpoint an area in the genome with significant linkage to the disease. In an independent meta-analysis, an overlapping region was rated as the second most significant genetic risk factor for schizophrenia in the genome. The candidate region identified by Sklar resides on the long arm of chromosome 5 (denoted 5q) and is quite large: it measures about 30 million nucleotides in length and contains hundreds of genes.
We began sorting through the list of genetic suspects and reported the results of our endeavors in the December 2005 issue of Molecular Psychiatry. A few prominent members on the roster, which encode subunits of the receptor for gamma-aminobutyric acid A (GABA-A), initially piqued our interest. They lie together in a cluster on chromosome 5q and include GABRA1, GABRB2, GABRG2, GABRA6 and GABRP. When pieced together, receptor subunits dwell at nerve endings in the brain, called synapses, and help to relay the signals carried by GABA. The GABA system has been previously implicated in schizophrenia based on the altered number of GABA receptor complexes in patients’ brains, for example. However, these findings have been largely unexplored in the few genetic analyses that have been performed.
Tracey Petryshen
Using single nucleotide polymorphisms (SNPs), we detected specific genetic signatures, called haplotypes, within several GABA-A receptor subunit genes that are common among schizophrenia patients from the Portuguese Islands. We confirmed the association with schizophrenia in a subset of these haplotypes, which occur in two genes, GABRA1 and GABRP, by examining an independent group of German patients. This gave us greater confidence that our findings were not false discoveries due to chance — a problem that plagues association studies of complex genetic disorders — but that they may indeed reflect a true genetic relationship between the GABA system and schizophrenia.
We next wondered if the presence of specific haplotypes could dictate changes in gene expression. By screening blood cell samples, we found that a haplotype in the GABRA1 gene corresponded to decreased amounts of one of its neighbors, GABRA6. We also looked for coordinate changes in the expression of groups of genes that are functionally related to members of the GABA-A receptor gene cluster. Using the Gene Set Enrichment Analysis (GSEA) method, we noted a correlation between haplotypes in the GABRA1 gene and the increased expression of two non-overlapping gene sets. One set is coexpressed with GABRA1 and contains genes that encode synaptic and vesicle-associated proteins. Some of these proteins, which fill prominent roles in the brain, are present at abnormal levels in the brains of schizophrenia patients. The second gene set functions in a network with GABRB2 and consists of many neurotransmitter receptor genes. Collectively, our findings implicate the GABA-A receptor gene cluster in schizophrenia and point to specific disease haplotypes, particularly in the GABRA1 gene, that may perturb the expression of GABA-related genes.
Now we are moving forward with our own analysis and encouraging others in the schizophrenia research community to examine distinct patient cohorts for the same haplotypes, which will tell us if there is a broad consensus in the genetics of the disease. We are also studying post-mortem samples to determine if the changes in gene expression that we detected in blood cells are also reflected in the brains of schizophrenia patients. Hopefully, future Spotlights will detail further progress in our effort to grasp schizophrenia’s genetic origins and perhaps will also fulfill my wish for greater understanding of the disorder and compassion for its sufferers.
Further Reading:
Petryshen TL et al. . Mol Psychiatry 2005 December;10(12):1074-1088. DOI:10.1038/sj.mp.4001739
Sklar P et al. . Mol Psychiatry 2004 February;9(2):213-218. DOI:10.1038/sj.mp.4001418
