JAMA Neurol. 2014 Dec;71(12):1514-9. doi: 10.1001/jamaneurol.2014.1663.

Common genetic variants on 6q24 associated with exceptional episodic memory performance in the elderly.

Sandra Barral, PhD1; Stephanie Cosentino, PhD1; Kaare Christensen, DMSc4; Anne B Newman, PhD3; Thomas T Perls, MD2; Michael A Province, PhD5; Richard Mayeux, MD, MSc1 for the Long Life Family Study (LLFS)

 

1G.H. Sergievsky Center and Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Columbia University Medical Center, Department of Neurology, 639 West 1168th Street, New York, NY 10032, USA
2Geriatrics Section, Section of Geriatrics, Department of Medicine, Boston University School of Medicine and Boston Medical Center, Boston, MA 02118, USA
3Department of Epidemiology, Graduate School of Public Health, A527 Crabtree Hall,130 DeSoto Street, Pittsburgh, PA 15261, USA
4The Danish Aging Research Center, University of Southern Denmark, Odense C, Denmark and Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark; and Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense C, Denmark.
5Data Management Coordinating Center, Washington University School of Medicine Division of Statistical Genomics, 4444 Forest Park Blvd., Campus Box 8506, St. Louis, Missouri 63108, USA

 

Abstract

Genetic influences on memory persist with age. Genome-wide linkage analysis in 18 families selected from among 554 families on the basis of having two or more offspring with exceptional episodic memory performance yielded evidence of linkage to chromosome 6q24. Single nucleotide polymorphisms (SNPs) at 6q24 were found to be associated with episodic memory performance in four independent datasets that included 4,000 non-demented elderly. Among the biological relevant genes in this chromosomal region is monooxygenase DBH-like 1 gene (MOXD1), implicated in the biosynthesis of norepinephrine prominently involved in cognitive functions. Our results provide strong evidence for potential candidate genes related to exceptional episodic memory on 6q24. Identifying exceptional episodic memory genes will help to understand the biological basis of memory performance and allow interventions for enhancement of cognitive function.

PMID: 25317765

 

Supplement

Why some individuals demonstrate a better memory performance in late life, while others do not remains an unanswered question. Results from the limited number of studies that have investigated the underlying factors of this exceptionality showed a strong genetic component (1), however no specific genes have been identified.

In order to investigate whether genetic variation may account for this variability, we used a cognitive endophenotype based on exceptional episodic memory performance (EEM) (2). We conducted a genome-wide linkage analysis in a set of long-lived families whose exceptional episodic memory abilities appeared to have a significant genetic influence and detected significant evidence of linkage to EEM on chromosome 6q24 (LOD=3.62, p=2.1 x 10-5).

In order to obtain an unbiased estimate of the genetic effect size, we used the entire distribution of episodic memory scores in four independent cohorts of non-demented and unrelated elderly individuals: The National Institute of Aging Late Onset Alzheimer Disease (NIA-LOAD), The Alzheimer Disease Neuroimaging Initiative (ADNI), The Alzheimer’s Disease Genetic Consortium (ADGC) and The Washington Heights Aging Project (WHICAP). We replicated the association between EEM and SNPs under this linkage region in four independent replication datasets (Figure 1). We also found that the strongest association with episodic memory occurs among individuals lacking an APOE-ε4 allele.

The region we identified on chromosome 6q24 contains several highly plausible biological candidate genes. Our strongest association was observed at SNP rs6902875, which is located 372bp downstream of the MOXD1 gene. This gene is involved in the biosynthesis of norepinephrine, a neurotransmitter expressed in brain areas involved in cognitive performance. Additional candidate genes include HSF2, heat shock factor protein 2, gene which contributes to neural plate induction in early mammalian central nervous system and brain development (3), and NKAIN2, the Na (+)/K(+)-transporting ATPase subunit beta-1-interacting protein gene that is part of a transmembrane protein family neuronally expressed in mouse brains and associated with human neurological phenotypes (4).

By selecting LLFS families demonstrating exceptional episodic memory, we were able to identify relevant QTLs in 6q24 chromosomal region and demonstrated that these common genetic variants can be extended to a related phenotype in the general population. Identifying genes responsible for exceptional episodic memory provides insights into biological pathways associated with memory performance and possible interventions for enhancement of cognitive function.

 

fig1

Figure 1. Linkage analysis and follow-up SNP association analyses.

1a) Multipoint linkage analyses on chromosome 6q24 in 18 LLFS families. LOD scores are plotted against the genetic distance in centimorgans (cM). Maximum LOD score of 3.62 is located at 145cM (139,011,233 bp). Follow-up SNP association’s analyses evaluated the 112-164-Mb region encompassing the linkage peak.

1b) Plot of the 6324 SNPs associated with exceptional memory in the LLFS families.

1c) APOE stratified meta-analysis of 26 candidate SNPs in all four replication cohorts (NIA-LOAD, ADNI, ADGC and WHICAP). SNP marker rs6902875, with the strongest association with episodic memory performance, is located downstream a potential candidate gene, MOXD1 (123bp).

 

References

  1. Haworth CM, Wright MJ, Martin NW, Martin NG, Boomsma DI, Bartels M, et al. A twin study of the genetics of high cognitive ability selected from 11,000 twin pairs in six studies from four countries. Behav Genet. 2009;39(4):359-70. PMCID: 2740717.
  2. Barral S, Cosentino S, Costa R, Andersen SL, Christensen K, Eckfeldt JH, et al. Exceptional memory performance in the Long Life Family Study. Neurobiol Aging. 2013.
  3. Walsh D, Li Z, Wu Y, Nagata K. Heat shock and the role of the HSPs during neural plate induction in early mammalian CNS and brain development. Cell Mol Life Sci. 1997;53(2):198-211.
  4. Yue Y, Stout K, Grossmann B, Zechner U, Brinckmann A, White C, et al. Disruption of TCBA1 associated with a de novo t(1;6)(q32.2;q22.3) presenting in a child with developmental delay and recurrent infections. J Med Genet. 2006;43(2):143-7. PMCID: 2564632.

 

 

 

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