Association of genetic variants on 15q12 with cortical thickness and cognition in schizophrenia

Abstract

Context: Cortical thickness is a highly heritable structural brain measurement, and reduced thickness has been associated with schizophrenia, bipolar disorder, and decreased cognitive performance among healthy control individuals. Identifying genes that contribute to variation in cortical thickness provides a means to elucidate some of the biological mechanisms underlying these diseases and general cognitive abilities.

Objectives: To identify common genetic variants that affect cortical thickness in patients with schizophrenia, patients with bipolar disorder, and controls and to test these variants for association with cognitive performance.

Design: A total of 597 198 single-nucleotide polymorphisms were tested for association with average cortical thickness in a genome-wide association study. Significantly associated single-nucleotide polymorphisms were tested for their effect on several measures of cognitive performance.

Setting: Four major hospitals in Oslo, Norway.

Participants: A total of 1054 case individuals and controls were analyzed in the genome-wide association study and follow-up cognitive study. The genome-wide association study included controls (n = 181) and individuals with DSM-IV -diagnosed schizophrenia spectrum disorder (n = 94), bipolar spectrum disorder (n = 97), and other psychotic and affective disorders (n = 49).

Main outcome measures: Cortical thickness measured with magnetic resonance imaging and cognitive performance as assessed by several neuropsychological tests.

Results: Two closely linked genetic variants (rs4906844 and rs11633924) within the Prader-Willi and Angelman syndrome region on chromosome 15q12 showed a genome-wide significant association (P = 1.1 x 10(-8) with average cortical thickness and modest association with cognitive performance (permuted P = .03) specifically among patients diagnosed as having schizophrenia.

Conclusion: This genome-wide association study identifies a common genetic variant that contributes to the heritable reduction of cortical thickness in schizophrenia. These results highlight the usefulness of cortical thickness as an intermediate phenotype for neuropsychiatric diseases. Future independent replication studies are required to confirm these findings.

Figure 1

Single nucleotide polymorphisms (SNPs) located within the genomic region deficient in Prader-Willi and Angelman syndromes are strongly associated with cortical thickness in schizophrenia. Schematic (top) of paternally (blue) and maternally (red) imprinted and non-imprinted (green) genes in region. LOC100128714 is a putative protein-coding gene with unknown imprinting status. −log₁₀(p-values) indicate the significance of the additive effect of the number of minor alleles of each SNP on average cortical thickness, while controlling for age and sex. A conservative Bonferroni corrected p-value threshold (dashed line) for genome-wide significance was set to p = 1.67 × 10⁻⁸.

Figure 2

rs4906844 genotype is associated with global cortical thinning that is more prominent in frontotemporal regions. Brain maps show −log₁₀(p-values) for the additive effect of the number of minor alleles on cortical thickness at each vertex, while controlling for age and sex.

Figure 3

rs4906844 genotype accounts for cortical thinning in schizophrenia versus healthy controls. Schizophrenia subjects were grouped by genotype and subjects with two copies of the minor allele (AA, n = 23) and to a lesser degree subjects with one copy (AG, n = 45) show significant cortical thinning relative to healthy controls. Schizophrenia subjects homozygous for the major allele (GG, n = 26) show no significant thinning relative to controls. Cortical maps show −log₁₀(p-values) for association between schizophrenia diagnosis and cortical thickness at each vertex, while controlling for age and sex.

Figure 4

Average (+ SD) cortical thickness varies in schizophrenia (p = 1.08 × 10⁻⁸) but not other diagnostic categories (p > 0.05) based on rs4906844 genotype. SCZ = schizophrenia, BD = bipolar disorder. Sample sizes of diagnostic categories are listed in parentheses.