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Posts Tagged ‘Genome-wide association study’

I mean, how many people are really needed to run a sufficiently powered genome-wide association study?  Are there enough people on the planet?  Heather J. Cordell’s review, Detecting gene-gene interactions that underlie human diseases, seems optimistic, but, at this point, it seems a valid question … at least if you want to detect gene-gene interactions.

“The historical lack of success in genetic studies of complex disease can largely be attributed, not to ignored biological interactions, but rather to under-powered studies that surveyed only a fraction of genetic variation …”

thanks for the pic heckyeahart

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Twin studies have long suggested that genetic variation is a part of healthy and disordered mental life.  The problem however – some 10 years now since the full genome sequence era began – has been finding the actual genes that account for this heritability.

It sounds simple on paper – just collect lots of folks with disorder X and look at their genomes in reference to a demographically matched healthy control population.  Voila! whatever is different is a candidate for genetic risk.  Apparently, not so.

The missing heritability problem that clouds the birth of the personal genomes era refers to the baffling inability to find enough common genetic variants that can account for the genetic risk of an illness or disorder.

There are any number of reasons for this … (i) even as any given MZ and DZ twin pair shares genetic variants that predispose them toward the similar brains and mental states, it may be the case that different MZ and DZ pairs have different types of rare genetic variation thus diluting out any similar patterns of variation when large pools of cases and controls are compared …  (ii) also, the way that the environment interacts with common risk-promoting genetic variation may be quite different from person to person – making it hard to find variation that is similarly risk-promoting in large pools of cases and controls … and many others I’m sure.

One research group recently asked whether the type of common genetic variation(SNP vs. CNV) might inform the search for the missing heritability.  The authors of the recent paper, “Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls” [doi:10.1038/nature08979] looked at an alternative to the usual SNP markers – so called common copy number variants (CNVs) – and asked if these markers might provide a stronger accounting for genetic risk.  While a number of previous papers in the mental health field have indeed shown associations with CNVs, this massive study (some 3,432 CNV probes in 2000 or so cases and 3000 controls) did not reveal an association with bipolar disorder.  Furthermore, the team reports that common CNV variants are already in fairly strong linkage disequilibrium with common SNPs and so perhaps may not have reached any farther into the abyss of rare genetic variation than previous GWAS studies.

Disappointing perhaps, but a big step forward nonetheless!  What will the personal genomes era look like if we all have different forms of rare genetic variation?

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An historic find has occurred in the quest (gold-rush, if you will) to link genome variation with brain structure-function variation.  This is the publication of the very first genome-wide (GWAS) analysis of individual voxels (voxels are akin to pixels in a photograph, but are rather 3D cubes of brain-image-space about 1mm on each side) of brain structure – Voxelwise genome-wide association study (vGWAS) [doi: 10.1016/j.neuroimage.2010.02.032] by Jason Stein and colleagues under the leadership of Paul M. Thompson, a  leader in the area of neuroimaging and genetics – well-known for his work on brain structure in twin and psychiatric patient populations.

In an effort to discover genes that contribute to individual differences in brain structure, the authors took on the task of statistically analyzing the some 31,622 voxels (per brain) obtained from high-resolution structural brain scans; with 448,293 Illumina SNP genotypes (per person) with minor allele frequencies greater than 0.1 (common variants); in 740 unrelated healthy caucasian adults.  When performed on a voxel-by-voxel basis, this amounts to some 14 billion statistical tests.

Yikes!  A statistical nightmare with plenty of room for false positive results, not to mention the recent disillusionment with the common-variant GWAS approach?  Certainly.  The authors describe these pitfalls and other scenarios wherein false data is likely to arise and most of the paper addresses the pros and cons of different statistical analysis strategies – some which are prohibitive in their computational demands.  Undaunted, the authors describe several approaches for establishing appropriate thresholds and then utilize a ‘winner take all’ analysis strategy wherein a single ‘most-associated winning snp’ is identified for each voxel, which when clustered together in hot spots (at P = 2 x 10e-10), can point to specific brain areas of interest.

Using this analytical approach, the authors report that 8,212 snps were identified as ‘winning, most-associated’ snps across the 31,622 voxels.  They note that there was not as much symmetry with respect to winning snps in the left hemispere and corresponding areas in the right hemisphere, as one might have expected.  The 2 most significant snps across the entire brain and genome were rs2132683 and rs713155 which were associated with white matter near the left posterior lateral ventricle.  Other notable findings were rs2429582 in the synaptic (and possible autism risk factor) CADPS2 gene which was associated with temporal lobe structure and rs9990343 which sits in an intergenic region but is associated with frontal lobe structure.  These and several other notable snps are reported and brain maps are provided that show where in the brain each snp is associated.

As in most genome-wide studies, one can imagine that the authors were initially bewildered by their unexpected findings.  None of the ‘usual suspects’ such as neurotransmitter receptors, transcription factors, etc. etc. that dominate the psychiatric genetics literature.  Bewildered, perhaps, but maybe thats part of the fun and excitement of discovery!  Very exciting stuff to come I’ll bet as this new era unfolds!

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Where da rodents kick it
Image by Scrunchleface via Flickr

A recent GWAS study identified the 3′ region of the liver- (not brain) expressed PECR gene (rs7590720(G) and rs1344694(T)) on chromosome 2 as a risk factor for alcohol dependency.  These results, as reported by Treutlein et al., in “Genome-wide Association Study of Alcohol Dependence” were based on a population of 487 male inpatients and a follow-up re-test in a population of 1024 male inpatients and 996 control participants.

The authors also asked whether lab rats who – given the choice between water-based and ethanol-spiked beverages over the course of 1 year – showed differential gene expression in those rats that were alcohol preferrers vs. alcohol non-preferring rats.  Among a total of 542 genes that were found to be differentially expressed in the amygdala and caudate nucleus of alcohol vs. non-alcohol-preferring rat strains,  a mere 3 genes – that is the human orthologs of these 3 genes – did also show significant association with alcohol dependency in the human populations.  Here are the “rat genes” (ie. human homologs that show differential expression in rats and association with alcohol dependency in humans): rs1614972(C) in the alcohol dehydrogenase 1C (ADH1C) gene, rs13273672(C) in the GATA binding protein 4 (GATA4) gene, and rs11640875(A) in the cadherin 13 (CDH13) gene.

My 23andMe profile gives a mixed AG at rs7590720, and a mixed GT at rs1344694 while I show a mixed CT at rs1614972, CT at rs13273672 and AG at rs11640875.  Boooring! a middling heterozygote at all 5 alcohol prefer/dependency loci.   Were these the loci for chocolate prefer/dependency I would be a full risk-bearing homozygote.

 

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slow motion video
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The neuregulin-1 (NRG1) gene is widely known as one of the most well-replicated genetic risk factors for schizophrenia.  Converging evidence shows that it is associated with schizophrenia at the gene expression and mouse model levels which are consistent with its molecular functions in neural development.   However, in several recent genome-wide association studies (GWAS), there appeared nary a blip of association at the 8p12 locus where NRG1 resides.  What gives?

While there are many possibilities for this phenomenon (some discussed here), the recent paper, “Support for NRG1 as a Susceptibility Factor for Schizophrenia in a Northern Swedish Isolated Population” by Maaike Alaerts and colleagues, suggest that the typical GWAS study may not adequately probe genetic variation at a fine enough scale – or, if you will, use a netting with sufficiently small holes.  By holes, I mean both the physical distance between genetic markers and the frequency with which they occur in populations.  While GWAS studies may use upwards of 500,000 markers – that’s a pretty fine scale net for a 3,000,000,000bp genome (about 6,000bp apart) – Alaerts and colleagues set forth with slightly finer-scale netting.  They focus on a 157kb region that is about 60kb upstream from the start of the NRG1 gene and construct a net consisting of 37 variants between the markers rs4268087 and rs17601950 (average spacing about 5kb).  They used the tagger program to select markers that account for all haplotypes whose frequency is higher than 1.5%.  Thus – even though there are still more than 500 possible snps in the region Alaerts and colleagues are exploring, they are using a slightly finer netting than a typical GWAS.

The results of their analysis (using GENEPOP) of 486 patients and 514 ethnically matched control participants from northern Sweden did reveal significant associations in an area slightly downstream (about 50kb closer to the start point of the NRG1 gene) than the location of the “previously often replicated variants”, suggesting that the region does confer some risk for schizophrenia, but, that diagnostic markers for such risk will be different for different populations.  More telling however are the very weak effects of the haplotypes that show significant association.  Those haplotypes with the most significance show meager differences in how often they are observed in patients vs. controls.  For example, one haplotype was observed in 5% of patients vs. 3% of controls. Others examples were, 11 vs. 9, 25 vs. 22 and 40% vs. 35% – revealing the very modest (krill sized) effects that single genetic variants can have in conferring risk toward mental illness.

However, there are potentially lots of krill in the genomic sea!

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