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Researchers Use HapMap to Cast Doubt on Dysbindin

13 October 2006. Researchers from Massachusetts General Hospital in Boston and the Broad Institute, a joint venture of Massachusetts Institute of Technology and Harvard University, have come to some potentially controversial conclusions in the field of schizophrenia susceptibility genes. Writing in the November issue of The American Journal of Human Genetics, Pamela Sklar and colleagues suggest that dysbindin (DTNBP1) may not be a susceptibility gene for schizophrenia, in disagreement with a number of previous studies.

The researchers utilized the most recent version of the International HapMap to construct a high-resolution map of the DTNBP1 genomic region. When haplotypes that had been previously identified by other groups as associated with schizophrenia risk were then mapped onto the high-resolution map, the researchers found no consensus. This suggested to the authors that the role of DTNBP1 in schizophrenia should be re-evaluated in large-scale studies using their new, high-resolution map.

Previous studies of DTNBP1
A number of heritability studies have been performed among patients with schizophrenia, but it has been difficult for researchers to identify replicable susceptibility genes across studies. Currently, there are several candidate genes for which there is either compelling or promising evidence (for review, see Ross et al., 2006; Straub and Weinberger, 2006). One of the genes with the most compelling evidence is dysbindin (DTNBP1).

DTNBP1 was first identified in a study of schizophrenia-affected Irish pedigrees (Straub et al., 2002; van den Oord et al., 2003); since that time, five other studies have found an association of schizophrenia with DTNBP1 in samples of European ancestry. What has been confusing with this data, however, is that the associated alleles and haplotypes have differed among samples. No definitive causal variant of DTNBP1 that contributes to schizophrenia risk has been identified. Adding to the confusion is the fact that the same single nucleotide polymorphisms (SNPs) have not been genotyped across the six studies, preventing direct comparisons.

Lead authors Mousumi Mutsuddi and Derek Morris and colleagues attempted to make the data from these six studies directly comparable by using data from the International HapMap project (see SRF related news story). The HapMap project has genotyped SNPs from 270 individuals, grouped into four, roughly geographical locations: Yoruba in Ibadan, Nigeria; Japanese in Tokyo, Japan; Han Chinese in Beijing, China; and Utah residents with ancestry from Northern and Western Europe (abbreviation: CEU; genotyped in 1980 by the Centre d’Étude du Polymorphisme Humain). The CEU sample comprised 30 parent-offspring trios.

Mutsuddi and colleagues constructed a high-resolution haplotype map for the DTNBP1 region by using the CEU sample from HapMap. To supplement the SNPs already identified by the HapMap project in this sample (113 SNPs), SNPs from two other sources were genotyped using CEU sample DNA. First, Mutsuddi and colleagues genotyped CEU sample DNA for all the SNPs reported in the six association studies (29 SNPs). Second, they genotyped the CEU sample for SNPs across the DTNBP1 region which were taken from the Single Nucleotide Polymorphism database (24 SNPs). Thus, the total number of SNPs on the finished map was 166.

The program Tagger (Haploview) was then used to determine tagging SNPs from this map. Because SNPs in close proximity tend to be inherited together, a single tagging SNP (tSNP) can stand as proxy for a grouping of several SNPs. Based on six key tSNPs, the researchers found that the CEU sample contained five common haplotypes in the DTNBP1 region. They constructed a phylogenetic tree to show how each haplotype evolved from a common, ancestral haplotype.

Comparing the studies
To compare the association studies to each other in reference to the CEU-derived haplotype phylogenetic tree, Mutsuddi and colleagues noted the SNPs in each study that defined the “associated” haplotype for that study. They then took each associated haplotype and mapped it onto the phylogenetic tree containing the most common five haplotypes in the CEU sample. They assumed that if a haplotype were truly associated with an increased risk of schizophrenia, there would be a consensus among the six studies on the phylogenetic tree.

In fact, that is not what they found. The association from Kirov and colleagues (Kirov et al., 2004) mapped to haplotypes 1, 2, 4, and 5. The association from Bray and colleagues (Bray et al., 2005) mapped to haplotypes 2 and 5. The association from Schwab and colleagues (Schwab et al., 2003) mapped to haplotypes 1 and 2. The association from van den Oord and colleagues (van den Oord et al., 2003) mapped to haplotype 3. The strongest associations from Van Den Bogaert and colleagues (Van Den Bogaert et al., 2003) and Funke and colleagues (Funke et al., 2004) mapped onto haplotype 4. In sum, each of the five most common haplotypes identified by a high-resolution SNP map of the DTNBP1 region in the CEU sample was found to be “associated” with risk of schizophrenia in one or another of the six studies.

Mutsuddi and colleagues also found that the haplotypes analyzed in the six studies were present in the CEU sample at roughly the same frequency. “This suggests that each European-derived sample is genetically similar and that population stratification cannot explain differences in published results,” they write.

“Because we find that all of the association samples of European-derived ancestry have a similar genetic structure, the conflicting results among studies cannot simply be attributed to population differences. This calls into question the interpretation of the replication studies at this locus,” the authors conclude. They called for further, large-scale studies using their high-density map to help determine how DTNBP1 contributes to schizophrenia susceptibility.—Jillian Lokere.

Reference:
Mousumi Mutsuddi, Derek W. Morris, Skye G. Waggoner, Mark J. Daly, Edward M. Scolnick, Pamela Sklar. Analysis of high-resolution HapMap of DTNBP1 (Dysbindin) suggests no consistency between reported common variant associations to schizophrenia. Published online Oct 3 in Am J Hum Genet. Abstract

Comments on Related News


Related News: Parsing Dysbindin’s Roles in the Brain

Comment by:  Antonieta Lavin
Submitted 9 November 2011
Posted 10 November 2011
  I recommend the Primary Papers

The findings by Shao and collaborators are very exciting, and since their preparation allows for very sophisticated genetic manipulations, the possibility of isolating and reversing the effects of lack of dysbindin in neurons and glia provide important insights into the function of this extremely interesting protein. One result of the study that is relevant for future therapeutic endeavors is the finding that adding glycine to the diet of mutant flies improved memory. We have shown (Glen et al., 2009) that adding glycine to the perfusion buffer of a hippocampal slice preparation from dysbindin-null mice (C57) restored the decreased LTP levels in the null mice without affecting LTP in the WT genotype. Moreover, Shao and colleagues' finding stresses the important role of dysbindin in regulating NMDA receptors. We have already demonstrated that NMDA currents are decreased in dysbindin-null mice, as is expression of the obligatory NMDA receptor subunit (NR1). Furthermore, the degree of NR1 expression directly correlates with performance on a spatial working memory task, providing a mechanistic explanation for cognitive changes previously associated with dysbindin expression (Karlsgodt et al., 2011). However, it will be necessary to investigate the molecular mechanisms mediating changes in glutamate and dopamine after deletion of dysbindin.

Recent experiments by us (Sagu et al.), to be presented this year at the Annual Meeting of the Society for Neuroscience, show that loss of dysbindin produces small, synaptic, releasable pools; elicits a deficit in synaptic vesicle dynamics; and decreases levels of proteins involved in priming of synaptic vesicles and in vesicle dynamics. Moreover, dysbindin-null mice exhibit a lower concentration of Ca++.

However, much remains to be known, as the study of this interesting gene and its related proteins is a deserving research field for understanding schizophrenia and bipolar disorder.

References:

Glen B., New, N.N. Mulholland, P., Chandler, J and Lavin, A. (2009) Dysbindin-1 mutation impairs synaptic plasticity in hippocampus: A successful recovery strategy through modulation of NMDA receptor function. Society for Neuroscience.

Karlsgodt KH, Robleto K, Trantham-Davidson H, Jairl C, Cannon TD, Lavin A, Jentsch JD. Reduced dysbindin expression mediates N-methyl-D-aspartate receptor hypofunction and impaired working memory performance. Biol Psychiatry . 2011 Jan 1 ; 69(1):28-34. Abstract

Sagu S. and Lavin A. (2011) Presynaptic effects of dysbindin mutation: Are SNARE complexes involved?. Society for Neuroscience, Washington, DC (386.07).

View all comments by Antonieta Lavin