If there are different alleles (a specific form of a gene) at a locus, and they occur in at least 1% of the population, this variant is considered “polymorphic” (i.e., many forms). DNA sequence variants at single nucleotides are known as single nucleotide polymorphisms (SNPs; pronounced “snips”). Variants that occur in less than 1% are termed rare variants. SNPs and other markers are heritable and allow us to test for disease association in families through linkage analysis and other approaches. In case-control studies, SNPs and/or hap- lotypes (a series of SNPs that are inherited as a group) with a statistically significant increased frequency in cases than in controls are deemed to be disease-associated. Because these analyses can involve tens of thousands to millions of SNP markers, statistical significance must be reached at stringent levels to avoid false-positive associations due to multiple comparisons (e.g.,
p < 10-8).
Genome-Wide Association Studies (GWAS)
Millions of SNPs have been identified through the International HapMap Project (hapmap.ncbi.nlm.nih.gov/). As noted earlier, these SNPs are located along the length of every human chromosome and can be used to identify disease-associated loci. GWAS are case-control association studies to identify disease genes throughout the genome. The use of high-density SNP arrays (e.g., 2.5 million SNPs) has become common.
Our initial efforts at large-population GWAS resulted in the creation of the International Schizophrenia Consortium (ISC). As part of this collaboration, we investigated possible copy number variants (CNVs) in schizophrenia. CNVs are deletions or duplications of a piece of a chromosome that changes the number of copies at a locus. Our results were not only consistent with already known deletions, but we also identified new deletions on chromosomes 1 and 15.13
Based on prior research, we focused our efforts on 22q11.2 deletions. Indeed, a known chromosomal anomaly related to psychosis was labeled the 22q11.2 deletion syndrome (22q11.2DS).14 In the ISC sample of more than 6,500 individuals, 13 individuals with schizophrenia were found to have large deletions (i.e., >500 kb) in the 22q11.2 region, with an odds ratio (OR) of 21.6 (empiric P = 0.0017; genome-wide corrected P = 0.0046).13 In addition, large deletions were identified on chromosomes 15q13.3 and 1q21.1.13 The 15q13.3 deletion (28-31 Mb) was observed in nine cases and no controls (empiric P = 0.0029; genome-wide corrected P = 0.046; OR = 17.9). A smaller but significantly elevated OR (6.6) was found for the 1q21.1 deletion (142.5-145.5 Mb).13 Ten cases and one control carried deletions (empiric P = 0.0076; genome-wide corrected P = 0.046). In total, large deletions at these three loci occurred in nearly 1% of the schizophrenia cases. These results have been independently confirmed.15