Posts tagged Copy number variation
I have written previously about CNV’s and how de novo CNV’s have been recently shown to correlate with disorders like autism and schizophrenia. I have also been militantly proposing that autism and psychosis are diametrically opposed disorders and have been gladdened to find that recent CNV data support that hypothesis. I reported how 16p11.2 duplications were associated with schizophrenia while micro-deletions at same site associated with autism. I also reported how a larger study which looked at multiple CNVs found the same reciprocal effects on CNV sites for autism and schizophrenia, thus bolstering the hypothesis that these are diametrically opposed.
By now you might be wondering what all this has to do with ADHD? Well, for one, early this year I started expanding my model and started conceptualizing ADHD as opposed to Autism in childhood and ADHD thus as belonging to psychotic spectrum; I mused that perhaps the same genetic vulnerability that leads to ADHD in childhood could lead to the manifestation of psychosis in teenage/adulthood. Its worthwhile noting that both ADHD and Psychosis are highly correlated with creativity.
So I could not stop my exuberance at finding that CNVs at another site 16p13.11 has been implicated in ADHD and the duplications are present in both ADHD and Schizophrenia. Also, as per the same study , ADHD children carry a large number of de novo CNV’s – a pattern similar ro Autism/schizophrenia. Some, for example the Neuroskeptic, have taken the same loci of CNVs to mean that these CNVs just confer a general risk of maladaptation, but I think they are missing the forest for the trees. The pattern points to the diametrical model and how CNvs are one mechanism in which tug-of-wars are played (whether evolutionary variation or parent-offspring or between paternal and maternal genomes).
Let me explain what I mean by tug-of-wars. Say you have a evolutionary trade-off between exploration and exploitation, with one extreme being useful in some extreme environmental niche (say food is abundant) and the other strategy useful in the opposed environmental niche (say food is scare) . The trait that gets stabilized should have a bell cure distribution so that the a species can survive even if environment leans toward one extreme. The way to archive this could be by having distribution of frequency of different alleles; or it can be via CNV mechanism. You may have some gentic loci for exploration and have a single popular gene allele that codes for exploration at that loci and CNVs that cause deletions here will lead to more exploitation while CNVs that are duplications will lead to more exploration. Thus, by CNV mechanism one can have more of good thing or less of a good thing, good depending on context (i.e context says what is ‘good’).
To take the example of 16p13.11 – it seems it is somehow related to mental retardation/ creativity/intelligence. A deletion at this site causes mental retardation/multiple congenital anomalies.=, while duplications have benign effects. I would conjecture that duplications (associated with ADHD and schizophrenia) may actually increase intelligence/ creativity. That woudl fit with the diametrical model and the finding that ADHD kids are more creative nd develop language more readily than autistic kids of same age.
I am pasting the background and findings from the abstract below:
Large, rare chromosomal deletions and duplications known as copy number variants (CNVs) have been implicated in neurodevelopmental disorders similar to attention-deficit hyperactivity disorder (ADHD). We aimed to establish whether burden of CNVs was increased in ADHD, and to investigate whether identified CNVs were enriched for loci previously identified in autism and schizophrenia.
Data for full analyses were available for 366 children with ADHD and 1047 controls. 57 large, rare CNVs were identified in children with ADHD and 78 in controls, showing a significantly increased rate of CNVs in ADHD (0·156 vs 0·075; p=8·9×10?5). This increased rate of CNVs was particularly high in those with intellectual disability (0·424; p=2·0×10?6), although there was also a significant excess in cases with no such disability (0·125, p=0·0077). An excess of chromosome 16p13.11 duplications was noted in the ADHD group (p=0·0008 after correction for multiple testing), a finding that was replicated in the Icelandic sample (p=0·031). CNVs identified in our ADHD cohort were significantly enriched for loci previously reported in both autism (p=0·0095) and schizophrenia (p=0·010).
To some the fact that ADHD had the same loci as both Autism and Schizophrenia may speak against there being a diametrical relation; however the same was claimed when initially it was found that autism and schizophrenia CNVs were at the same loci; only after looking at the nature of CNV’s (whether duplications or deletions) were the researchers able to identify the diametrical nature of the CNV’s
I haven’t read the full paper yet (waiting for someone to send me the paper) and as and when I get my hands on the full paper, I’ll update this blog post with more details.
Williams, N., Zaharieva, I., Martin, A., Langley, K., Mantripragada, K., Fossdal, R., Stefansson, H., Stefansson, K., Magnusson, P., & Gudmundsson, O. (2010). Rare chromosomal deletions and duplications in attention-deficit hyperactivity disorder: a genome-wide analysis The Lancet DOI: 10.1016/S0140-6736(10)61109-9
There is a letter published in the advance online edition of Nature Genetics, that reports that microduplication of genes in the region 16p11.2 are associated with the risk of schizophrenia in a large cohort. It has been earlier shown that microdeletions in the same region confer the risk of Autism.Thus, it seems that the region codes for genes too much of which causes schizophrenia and too little autism. Here is the abstract of the study:
Recurrent microdeletions and microduplications of a 600-kb genomic region of chromosome 16p11.2 have been implicated in childhood-onset developmental disorders. We report the association of 16p11.2 microduplications with schizophrenia in two large cohorts. The microduplication was detected in 12/1,906 (0.63%) cases and 1/3,971 (0.03%) controls (P = 1.2 times 10-5, OR = 25.8) from the initial cohort, and in 9/2,645 (0.34%) cases and 1/2,420 (0.04%) controls (P = 0.022, OR = 8.3) of the replication cohort. The 16p11.2 microduplication was associated with a 14.5-fold increased risk of schizophrenia (95% CI (3.3, 62)) in the combined sample. A meta-analysis of datasets for multiple psychiatric disorders showed a significant association of the microduplication with schizophrenia (P = 4.8 times 10-7), bipolar disorder (P = 0.017) and autism (P = 1.9 times 10-7). In contrast, the reciprocal microdeletion was associated only with autism and developmental disorders (P = 2.3 times 10-13). Head circumference was larger in patients with the microdeletion than in patients with the microduplication (P = 0.0007).
Here is what medical news today (via which I found this article) has to say about the findings:
An international team of researchers led by geneticist Jonathan Sebat, Ph.D., of Cold Spring Harbor Laboratory (CSHL), has identified a mutation on human chromosome 16 that substantially increases risk for schizophrenia.
The mutation in question is what scientists call a copy number variant (CNV). CNVs are areas of the genome where the number of copies of genes differs between individuals. The CNV is located in a region referred to by scientists as 16p11.2. By studying the genomes of 4,551 patients and 6,391 healthy individuals, Sebat’s team has shown that having one extra copy of this region is associated with schizophrenia. The study appears online today ahead of print in the journal Nature Genetics.
Schizophrenia and autism: two sides of the same coin?
“This is not the first time that the 16p11.2 region has caught our eye,” says Sebat. It was previously spotted in a 2007 study with Professor Michael Wigler at CSHL — a deletion of the identical region was identified in a girl with autism. Studies by several other groups have shown that losing one copy of 16p11.2 confers high risk of autism and other developmental disorders in children.
Taken together these studies suggest that some genes are shared between schizophrenia and autism, according to Sebat and colleagues. “In some ways, we might consider the two disorders to be at opposite ends of the same neurobiological process” says Shane McCarthy, Ph.D., the lead author of the study, “and this process is influenced by the copy number of genes on chromosome 16.” One hypothesis is that the loss of 16p11.2 leads to the deprivation of key genes involved in brain development, while an extra copy of this region might have the opposite effect.
A correlation between 16p11.2 mutations and head size
It is not known what biological processes are affected by the copy number of 16p11.2, Sebat notes. He believes, however, that the team may have stumbled on to an important clue. By studying the clinical records of patients, they discovered that patients with deletions of the region differ significantly in head size from those with duplications of the same region. Sebat reports, “Head circumference of patients with the deletion were larger than average by more than one standard deviation. Head circumference was slightly below average in patients with the duplication.” These findings, he notes, are consistent with some previous studies that have observed a trend towards larger brain size in autism and an opposite trend toward smaller brain size in schizophrenia.
All this nicely fits in with what I have been proclaiming from the rooftops from the early days of this blog: that autism and Schizophrenia are opposites on the same continuum and the genes involved should also be the same. More copy numbers leading to propensity towards psychosis while lesser number or deletions associated with autistic traits. One more puzzle piece fits in and now we know why the brain size differences exist in autistic and schizophrenic persons and what the poetntial function (mentalizing) of region 16p11.2 may be.
McCarthy, S., Makarov, V., Kirov, G., Addington, A., McClellan, J., Yoon, S., Perkins, D., Dickel, D., Kusenda, M., Krastoshevsky, O., Krause, V., Kumar, R., Grozeva, D., Malhotra, D., Walsh, T., Zackai, E., Kaplan, P., Ganesh, J., Krantz, I., Spinner, N., Roccanova, P., Bhandari, A., Pavon, K., Lakshmi, B., Leotta, A., Kendall, J., Lee, Y., Vacic, V., Gary, S., Iakoucheva, L., Crow, T., Christian, S., Lieberman, J., Stroup, T., Lehtimäki, T., Puura, K., Haldeman-Englert, C., Pearl, J., Goodell, M., Willour, V., DeRosse, P., Steele, J., Kassem, L., Wolff, J., Chitkara, N., McMahon, F., Malhotra, A., Potash, J., Schulze, T., Nöthen, M., Cichon, S., Rietschel, M., Leibenluft, E., Kustanovich, V., Lajonchere, C., Sutcliffe, J., Skuse, D., Gill, M., Gallagher, L., Mendell, N., Craddock, N., Owen, M., O’Donovan, M., Shaikh, T., Susser, E., DeLisi, L., Sullivan, P., Deutsch, C., Rapoport, J., Levy, D., King, M., & Sebat, J. (2009). Microduplications of 16p11.2 are associated with schizophrenia Nature Genetics DOI: 10.1038/ng.474
UPDATE: I just revisited my 20th may 2008 post on the matter and realized how prophetic my musings were. Reproducing part of it below the fold for the benefit of newbies to this blog:
CNVs on the other hand present a different model of disease. One can have one or more types of CNVs (deletions, duplications, multiple duplications etc) associated with the same genetic code sequence and this in my view would lead to spectrum like diseases where one may find variations along a continuum on a particular trait- based on how many copies of the genetic sequence one has. One would remember that I adhere to a spectrum based view of schizophrenia/psychosis and also a spectrum based view of Autism. Moreover I believe that Schizophrenia and Autism are the opposite ends of the spectrum, whose middle is normalcy and that the appropriate traits may have to do with social brain, creativity etc.
now as it happen previous research has also found that CNVs are also found to a higher extent in autistics. Moreover, research has indicated that the same chromosomal regions have CNVs in both Autism and Schizophrenia. To me this is exciting news. Probably the chromosomal region (neurexin related is one such region) commonly involved in both schizophrenia and autism is related to cognitive style, creativity and social thinking. Qualitatively (deletions as opposed to duplications) and quantitatively (more duplications) different type of CNVs may lead to differential eruption of either Schizophrenia or Autism as the same underlying neural circuit gets affected due to CNVs, though in a different qualitative and quantitative way.