There are at least two models of the genetic architecture of schizophrenia characterized by both the frequency and penetrance of risk alleles. The common disease-common allele hypothesis emphasizes the importance of relatively common alleles, each with a small effect, acting together to increase disease risk. The common disease-rare alleles model emphasizes the impact of individually rare, yet highly penetrant alleles. Most likely is that both common and rare alleles contribute to the risk of schizophrenia, although the relative impact of each remains unknown.
Recent data have shown that rare structural mutations leading to an altered copy number of dosage-sensitive genes can lead to the development of neuropsychiatric disorders. For instance, large-scale genome scans have identified several schizophrenia-associated CNVs at 1q21.1, 2p16.3, 15q11.2 and 15q11.3, 16p11.2, 17p12 and 22q11.2.
The report of increased CNV burden in schizophrenia has led to the suggestion that perhaps the same phenomenon may hold for rare de novo highly penetrant single gene mutations.
A Canadian group recently published a paper in PNAS that explores this idea. We'll talk about it some more tomorrow.
