World Congress in Psychiatric Genetics 2011
I'm on my way back from the 2011 World Congress in Psychiatric Genetics, so here's a brief subjective account of some aspects of where the field seems to be.
Methodology
Results from sequencing studies, particularly whole-exome sequencing, are starting to trickle through. They are likely to turn into a flood over the next year. Sequencing studies carry the promise of finally being able to detect rare DNA changes having a really major effect on disease risk. Some concerns exist that sequencing studies confined to the exome may miss important mutations in non-coding regions. It remains to be seen how severe this problem will be in practice. Sequencing the genome rather than the exome is more expensive and yields vast amounts of data which may be difficult to interpret. Even with exome sequencing, a major challenge will be how to recognize which are likely to be disease-relevant mutations among the many thousands of variants each subject will possess. With sequencing studies we can expect to find pathogenic variants but the challenge will be to know that we have found them.
It is probably fair to say that there is a growing realisation that chip-based genome-wide SNP studies can only detect common variants with a minor effect on risk. Alongside this is some refocussing on the task to identify rare variants with major effect size. It can be expected that sequencing studies will make a major contribution to this. There is little or no suggestion so far that the genes already identified as having common minor effects will also be found to harbour rare pathogenic mutations.
Interest continues in chromosomal deletions and duplications as rare but important risk factors in autism and schizophrenia. Some studies have looked at these variants arising de novo rather than being inherited. Although such de novo events seem to produce disease in some individuals it remains the case that in others inherited variants act as risk factors. Considering the genetic epidemiology of these conditions, it is clear that inherited factors make a major contribution to risk. Hence the study of de novo mutations occurring in random positions may not add substantially to our understanding.
Autism
The role for chromosomal insertions and deletions - copy number variants - as occasional causes of autism is further consolidated. Each of these chromosomal abnormalities disrupts the functioning of a number of genes and in most cases it is not clear which individual gene is responsible for the autism risk. However there were also reports of a small number of sequence variants in specific genes and these could probably be added to the list of those already known to be occasionally mutated in autism.
Schizophrenia
As for autism, the role for copy number variants as rare causes of schizophrenia is consolidated and is now accepted as an established finding. Again, no additional individual genes are specifically implicated although it was claimed that evidence pointed to the involvement of genes coding for proteins present in the synapse. Thus there is a developing notion that schizophrenia may be a disease of disturbed synaptic functioning.
From chip-based genome-wide association studies, it seems that there is still only one gene implicated in which common variation produces a minor effect on risk of schizophrenia. And nobody seems to have any idea what this gene does.
There are not yet convincing reports of rare sequence variants in specific genes having an aetiological role in schizophrenia. It is hoped that some may be identified through sequencing studies of large numbers of cases.
Bipolar disorder
By contrast with schizophrenia, it is probably fair to say that copy number variants do not make a substantial contribution to bipolar disorder.
Genes previously implicated as having a minor effect on risk of bipolar disorder continue to be supported, along with one or two others. Those previously identified consist of CACNA1C and ANK3. CACNA1C codes for a subunit of a calcium channel and there is some evidence also to implicates genes coding for other subunits of this ion channel and other related proteins. Indeed, the product of ANK3 seems to be involved in the functioning of this channel. Thus one could build up the picture that bipolar disorder might involve abnormal functioning of this calcium channel, which fits nicely with reports that calcium channel blockers can be effective treatments for bipolar disorder. The genetic variation so far identified in these genes consists of common variation with a small effect on risk. There is not yet any convincing report of a variant having a major effect which could be described as causing the illness. Again, it is hoped that such variants may be identified by sequencing studies which are getting underway.
Alzheimer's disease
A few more genes in which common variation affects risk of late onset Alzheimer's disease have been fairly convincingly identified, bringing the total to around ten. However with the exception of APOE the magnitude of the effect is very small. Nevertheless, these findings may be useful in terms of directing attention to a possible role for novel pathogenic processes involving inflammation.
Late onset Alzheimer's disease demonstrates less in the way of familial clustering than do schizophrenia and bipolar disorder. Thus there does not seem to particularly be the expectation that important rare variants will eventually be discovered in addition to the common ones already found.
Methodology
Results from sequencing studies, particularly whole-exome sequencing, are starting to trickle through. They are likely to turn into a flood over the next year. Sequencing studies carry the promise of finally being able to detect rare DNA changes having a really major effect on disease risk. Some concerns exist that sequencing studies confined to the exome may miss important mutations in non-coding regions. It remains to be seen how severe this problem will be in practice. Sequencing the genome rather than the exome is more expensive and yields vast amounts of data which may be difficult to interpret. Even with exome sequencing, a major challenge will be how to recognize which are likely to be disease-relevant mutations among the many thousands of variants each subject will possess. With sequencing studies we can expect to find pathogenic variants but the challenge will be to know that we have found them.
It is probably fair to say that there is a growing realisation that chip-based genome-wide SNP studies can only detect common variants with a minor effect on risk. Alongside this is some refocussing on the task to identify rare variants with major effect size. It can be expected that sequencing studies will make a major contribution to this. There is little or no suggestion so far that the genes already identified as having common minor effects will also be found to harbour rare pathogenic mutations.
Interest continues in chromosomal deletions and duplications as rare but important risk factors in autism and schizophrenia. Some studies have looked at these variants arising de novo rather than being inherited. Although such de novo events seem to produce disease in some individuals it remains the case that in others inherited variants act as risk factors. Considering the genetic epidemiology of these conditions, it is clear that inherited factors make a major contribution to risk. Hence the study of de novo mutations occurring in random positions may not add substantially to our understanding.
Autism
The role for chromosomal insertions and deletions - copy number variants - as occasional causes of autism is further consolidated. Each of these chromosomal abnormalities disrupts the functioning of a number of genes and in most cases it is not clear which individual gene is responsible for the autism risk. However there were also reports of a small number of sequence variants in specific genes and these could probably be added to the list of those already known to be occasionally mutated in autism.
Schizophrenia
As for autism, the role for copy number variants as rare causes of schizophrenia is consolidated and is now accepted as an established finding. Again, no additional individual genes are specifically implicated although it was claimed that evidence pointed to the involvement of genes coding for proteins present in the synapse. Thus there is a developing notion that schizophrenia may be a disease of disturbed synaptic functioning.
From chip-based genome-wide association studies, it seems that there is still only one gene implicated in which common variation produces a minor effect on risk of schizophrenia. And nobody seems to have any idea what this gene does.
There are not yet convincing reports of rare sequence variants in specific genes having an aetiological role in schizophrenia. It is hoped that some may be identified through sequencing studies of large numbers of cases.
Bipolar disorder
By contrast with schizophrenia, it is probably fair to say that copy number variants do not make a substantial contribution to bipolar disorder.
Genes previously implicated as having a minor effect on risk of bipolar disorder continue to be supported, along with one or two others. Those previously identified consist of CACNA1C and ANK3. CACNA1C codes for a subunit of a calcium channel and there is some evidence also to implicates genes coding for other subunits of this ion channel and other related proteins. Indeed, the product of ANK3 seems to be involved in the functioning of this channel. Thus one could build up the picture that bipolar disorder might involve abnormal functioning of this calcium channel, which fits nicely with reports that calcium channel blockers can be effective treatments for bipolar disorder. The genetic variation so far identified in these genes consists of common variation with a small effect on risk. There is not yet any convincing report of a variant having a major effect which could be described as causing the illness. Again, it is hoped that such variants may be identified by sequencing studies which are getting underway.
Alzheimer's disease
A few more genes in which common variation affects risk of late onset Alzheimer's disease have been fairly convincingly identified, bringing the total to around ten. However with the exception of APOE the magnitude of the effect is very small. Nevertheless, these findings may be useful in terms of directing attention to a possible role for novel pathogenic processes involving inflammation.
Late onset Alzheimer's disease demonstrates less in the way of familial clustering than do schizophrenia and bipolar disorder. Thus there does not seem to particularly be the expectation that important rare variants will eventually be discovered in addition to the common ones already found.
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