Evidence of genetic linkage for schizophrenia at chromosome 15q14 has been reported in nine independent studies, but the molecular variants responsible for transmission of genetic risk are unknown. National Institute of Mental Health Schizophrenia Genetics Initiative families were genotyped for single nucleotide polymorphisms (SNPs) and dinucleotide repeat markers in the 15q14 linkage region and analyzed based on the presence of particular alleles of the dinucleotide repeat marker D15S165 in the 15q14 region. Two alleles showed both familial transmission disequilibrium and population-wide association with schizophrenia. The two groups identified by these two D15S165 alleles differ in age of onset, number of hospitalizations and intensity of nicotine abuse, as well as in predominant ethnicity. Variations in the frequency of SNPs in CHRNA7, the alpha-7-nicotinic acetylcholine receptor subunit gene at 15q14, were found in each group. Further sequencing in these two groups may yield more definitive identification of the molecular pathology.