A genome-wide survey of human short-term memory

Abstract

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the α subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.

Figure 1

Genome-wide association and replication. Upper panel: genome-wide results (−log₁₀P), corrected for genome-wide multiple comparisons (false discovery rate (FDR)), are shown in chromosomal order for individually genotyped single-nucleotide polymorphisms (SNPs) that were tested for association with immediate verbal recall performance in the phase 1 sample of 333 individuals. The red dotted line indicates the FDR-corrected significance level, which was exceeded by six SNPs. Lower panel: list of significant SNPs (FDR-corrected) with corresponding chromosomal positions and phase 1 significance values. Chromosomal positions were retrieved from the March 2006 UCSC genome browser assembly. MAF, minor allele frequency; r, genotype-phenotype correlation in phase 1 sample; P, uncorrected significance level in phase 1 sample. The additive model was used for all association tests. The color reproduction of this figure is available on the html full text version of the manuscript.

Figure 2

Significant SCN1A allele-dependent differences in brain activation during a two-back working memory task. (a) Heterozygous carriers of the minor allele C showed significantly increased brain activations compared with homozygous A allele carriers in the right superior frontal gyrus/sulcus (BA 6). (b) Homozygous A allele carriers showed significantly increased brain activations compared with heterozygous individuals in the right inferior frontal sulcus (BA 44). Activations were overlaid on sagittal, coronal and horizontal sections of a T1-weighted magnetic resonance image of SPM2 and showed in color-coded t-values. Threshold: P<0.001, uncorrected for multiple comparisons.