Gerald Fishbach is Probably Right! Read On to understand the connection.

"It may be a quantitative issue - more or less gene expression rather than a yes or no matter. Deletions in autism and duplications in schizophrenia of the same piece of DNA is an astounding finding!"




One gene, many diseases
28 February 2008 16:34:00 EST Could the same genetic factors that cause autism also be responsible for bipolar disease, schizophrenia and other mental illnesses?

I was at an autism conference in Santa Fe this week and among the many fascinating things I learned, this was one that really piqued my interest.

In the last year, the idea that copy number variations (CNVs) are associated with autism has really taken hold among researchers. These CNVs are deletions or duplications of a chunk of DNA, and they may cause diseases by affecting the dosage — too much or too little — of a particular gene product.

Jonathan Sebat, who last year published one of the first CNV/autism papers, says the rate at which CNVs appear is about 100-fold higher than for single nucleotide polymorphisms (in which a single base of the genetic sequence is altered).

There are particular spots in the genome – “hotspots” if you will – that are prone to these deletions and duplications. Sebat says what this means is that, in essence, humans are a lot more genetically different than we previously thought and a large proportion of that difference is because of CNVs.

In January, one group of scientists published evidence that CNVs are found more often in people with autism (1%) than in controls (0.01%) and identified one potential hotspot on chromosome 16. At the meeting in Santa Fe, Sebat said that deletions in that same zone, and in a few others also implicated in autism, are also seen in people with schizophrenia.

What’s more, he says, in some families with inherited duplications of the chromosome 16 hotspot, there is a history of different psychiatric illnesses, suggesting that some CNV risk factors may be shared between these different illnesses.

There are similar overlaps in genes that have been implicated in autism, schizophrenia and bipolar disorder. Mining samples from people with schizophrenia and bipolar disorder for CNVs would help answer whether what Sebat and his colleagues have observed is a real phenomenon.

Not everyone was sold on this hypothesis, however.

Huda Zoghbi, famous for solving the genetic puzzle underlying the autism-like Rett Syndrome, noted that the 16p CNVs are sometimes seen in controls, and that even in families with a history of autism, not all affected individuals have the deletion.

Zoghbi’s point is that even if these CNVs are not benign and may increase the risk of autism – which would be consistent with the fact they are seen at higher rates in those with autism – a lot more evidence would be needed to prove that they cause autism.
posted by ApoorvaMandavilli
Comments
by GeraldFischbach 16 days ago
Neuropsychiatric disorders were defined based on an astute clinical observation more than half a century ago. Molecular analyses seem now to be showing that certain facets of such disorders may share common mechanisms. Is the cognitive deficit in schizophrenia different on a molecular or circuit level than the cognitive deficit in autism? In any case, we must consider that the same genetic lesions may be involved in both. It may be a quantitative issue - more or less gene expression rather than a yes or no matter. Deletions in autism and duplications in schizophrenia of the same piece of DNA is an astounding finding!



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What about Paternal Age and Spontaneous Mutations? How Old Were the Fathers?


Meredith Wadman 9 January 2008 17:00:00 EST
Differences in the number of copies of a chromosome 16
sequence may cause autism.
Roughly 10 percent of autism cases that occur as part of other clearly defined disorders, such as Rett or fragile X syndromes, have an obvious genetic cause.

What of the other 90 percent?

Mark Daly and his colleagues have hunted down a 593 kilobase ‘hot spot’ of genetic sequence that, when duplicated or deleted, substantially boosts the risks of autism seen independent of other syndromes.

In a paper published today by The New England Journal of Medicine 1, the researchers have identified a segment containing 25 genes on chromosome 16 that was deleted or duplicated in roughly one percent of children with autism. The results are based on samples drawn from three different populations in three independently conducted studies.

“It’s a beautiful paper that demonstrates a clear association between a genetic locus and autism,” says Arnold Levine, a molecular biologist who heads the Simons Center for Systems Biology at the Institute for Advanced Study at Princeton University.

Unlike his predecessors, Daly and his team didn’t simply identify a suspect region, but found it in numerous affected individuals, Levine notes. “This paper has been held to a higher standard,” Levine says. “It asked for reproducibility of observations and it got it. That’s the power of this paper.”

The finding provides unequivocal evidence that these genetic variations are a risk factor for autism, says Daly, an assistant professor of medicine at Massachusetts General Hospital and Harvard Medical School and an associate member of the Broad Institute in Cambridge, Massachusetts.

Using sophisticated gene-scanning technology from Affymetrix, Daly hunted for instances in which an individual carries fewer or more than the standard two copies of any given gene. This so-called ‘copy number variation’ — which boils down to the duplication or deletion of a genetic sequence — became a hot area in autism research following the publication last year of a paper in Science 2. That paper, written by Mike Wigler and Jonathan Sebat at Cold Spring Harbor Laboratory and their colleagues, reported a laundry list of de novo — meaning new or non-inherited — copy number variations in individual children with autism.

Using DNA samples from 1,441 subjects with autism from the Autism Genetic Resource Exchange, Daly found five de novo deletions and seven duplications in that specific region of chromosome 16, a rate of nearly one percent.

“The fact that it’s been identified as a de novo event, and that it’s recurrent — that is, that they found it in one percent of patients with autism — is the exciting part,” says Evan Eichler, a Howard Hughes Medical Institute investigator at the University of Washington in Seattle who wrote an accompanying commentary on the Daly paper. “So it’s not a transmitted mutation from grandparents to parents to offspring. This is something that is happening in the germ line.”

Repeat occurrence
Daly’s team also examined the DNA from two more sets of cases and controls, one from Boston Children’s Hospital and the other from deCODE genetics in Iceland. The same chunk of chromosome 16 was duplicated or deleted in substantially greater numbers in autistic subjects from these groups than in controls. Among all three groups, deletions and duplications in the region occurred in roughly one percent of subjects with autism; among controls it was close to zero.

“Because we see this specific event many, many times in many, many patients and hardly at all in the general population, we know specifically that this event has great importance to autism,” Daly says.

Sebat says Daly’s findings further legitimize the notion that although autism is heritable, spontaneous mutations have an important role in causing the disorder. “The kids with the [chromosome] 16p deletions, most of their risk comes from that single, primary insult,” Sebat says. “The six-word message is: ‘heritable’ does not always mean inherited.”

The finding is likely to have immediate, practical implications for diagnosis of autism and for genetic counseling, Sebat says. “If you know a first child is carrying a de novo deletion in this region of chromosome 16, the chance of a second child having the same deletion is low.”

The role of the newly flagged region in autism remains mysterious. Of the 25 genes, ranging from some expressed in the brain to others that are important for the immune system, “there’s nothing obvious,” to autism’s causation, says Daly. Still, they provide a tantalizing way forward. The MAPK3 gene in the region, for instance, codes for a regulatory protein involved in cell growth and brain wiring.

Important as the new results are, however, they are unlikely to yield a one-size-fits-all answer for autism. For instance, five children in four of the families had de novo deletions of the relevant region of chromosome 16. But three other autistic children in the same families did not have the deletion.

“There are going to be other genes and maybe even environmental factors that modify the phenotype,” Levine says. “It isn’t going to be so simple as to say, ‘this gene causes this disease’.”

References:
Image reproduced without permission, for educational purposes only, according to the Fair Use doctrine.

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Weiss L.A. et al. N. Engl. J. Med. 10.1056/NEJMoao75974 ↩

Sebat J. et al. Science 316, 445-449 (2007) PubMed ↩


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doi:10.1016/j.euroneuro.2007.01.004
Copyright © 2007 Elsevier B.V. All rights reserved.

Short communication
Additional support for linkage of schizophrenia and bipolar disorder to chromosome 3q29

Alexandra Schossera, , , Karoline Fuchsb, c, Theresa Scharld, Friedrich Leischd, e, Ursula Bailera, Siegfried Kaspera, Werner Sieghartb, c, Kurt Hornikf and Harald N. Aschauera
aDepartment of General Psychiatry, University Hospital for Psychiatry, Medical University Vienna, Austria
bDivision of Biochemical Psychiatry, University Hospital for Psychiatry, Medical University Vienna, Austria
cCenter for Brain Research, Division of Biochemistry and Molecular Biology, Medical University of Vienna, Austria
dDepartment of Statistics and Probability Theory, Vienna University of Technology, Austria
eDepartment of Statistics, University of Munich, Germany
fDepartment of Statistics and Mathematics, Vienna University of Economics and Business Administration, Austria
Received 9 August 2006; revised 15 January 2007; accepted 24 January 2007. Available online 6 March 2007.



Abstract
After publishing a genome scan and follow-up fine mapping, suggesting schizophrenia and bipolar disorder linkage to chromosome 3q29, we now genotyped 11 additional SNPs (single nucleotide polymorphisms), in order to narrow down a potential candidate region. Linkage was performed using the GENEHUNTER program version 2.1r3.

A NPL score Zall of 3.891 (p = 0.000156) was observed with SNP rs225. In short, we found significant linkage scores most telomeric on chromosome 3q29, spanning 3.46 Mbp (7 SNPs).

Keywords: Schizophrenia; Bipolar disorder; Linkage; Chromosome 3q29


Corresponding author. Department of General Psychiatry, University Hospital for Psychiatry, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Tel.: +43 1 40400 3543; fax: +43 1 40400 3629.


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Abstract
Background: Despite the widely accepted view that schizophrenia and bipolar disorder represent independent illnesses and modes of inheritance, some data in the literature suggest that the diseases may share some genetic susceptibility. The objective of our analyses was to search for vulnerability loci for the two disorders.
Methods: A genomewide map of 388 microsatellite DNA markers was genotyped in five schizophrenia and three bipolar disorder Austrian families. Linkage analyses was used to compute the usual parametric logarithm of the likelihood of linkage (LOD) scores and nonparametric linkage analysis (NPL scores Zall) was used to assess the pattern of allele sharing at each marker locus relative to the presence of the disease (GENEHUNTER). Affected status was defined as severe affective disorder or schizophrenia.

Results: Across the genome, p values associated with NPL scores resulted in evidence (i.e., p < .0007) for linkage at marker D3S1265 on chromosome 3q (NPL score Z all = 3.74, p = .0003). Two other markers (on 3q and 6q) showed p values of < .01.

Conclusions: We detected a potential susceptibility locus for bipolar disorder and schizophrenia on chromosome 3q, which has not been reported previously. The possibility of a false positive result has to be taken into account. Our data suggest shared loci for schizophrenia and bipolar affective disorders and are consistent with the continuum model of psychosis.


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Human Molecular Genetics Advance Access originally published online on December 21, 2007
Human Molecular Genetics 2008 17(4):628-638; doi:10.1093/hmg/ddm376
This Article




PubMed

PubMed Citation
Articles by Kumar, R. A.
Articles by Christian, S. L.

© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Recurrent 16p11.2 microdeletions in autism
Ravinesh A. Kumar1, Samer KaraMohamed1, Jyotsna Sudi1, Donald F. Conrad1, Camille Brune5, Judith A. Badner4, T. Conrad Gilliam1, Norma J. Nowak6, Edwin H. Cook, Jr5, William B. Dobyns1,2,3 and Susan L. Christian1,*
1 Department of Human Genetics 2 Department of Neurology 3 Department of Pediatrics 4 Department of Psychiatry, University of Chicago, Chicago, IL 60637, USA 5 Department of Psychiatry, University of Illinois at Chicago, Chicago, IL 60612, USA 6 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14236, USA

* To whom correspondence should be addressed at: Department of Human Genetics, University of Chicago, 920 East 58th Street, CLSC 319, Chicago, IL 60637, USA. Tel: +1 7738342971; Fax: +1 7738348470; Email: schrist@bsd.uchicago.edu

Received November 21, 2007; Accepted December 19, 2007

Autism is a childhood neurodevelopmental disorder with a strong genetic component, yet the identification of autism susceptibility loci remains elusive. We investigated 180 autism probands and 372 control subjects by array comparative genomic hybridization (aCGH) using a 19K whole-genome tiling path bacterial artificial chromosome microarray to identify submicroscopic chromosomal rearrangements specific to autism. We discovered a recurrent 16p11.2 microdeletion in two probands with autism and none in controls. The deletion spans 500-kb and is flanked by 147-kb segmental duplications (SDs) that are >99% identical, a common characteristic of genomic disorders. We assessed the frequency of this new autism genomic disorder by screening an additional 532 probands and 465 controls by quantitative PCR and identified two more patients but no controls with the microdeletion, indicating a combined frequency of 0.6% (4/712 autism versus 0/837 controls; Fisher exact test P = 0.044). We confirmed all 16p11.2 deletions using fluorescence in situ hybridization, microsatellite analyses and aCGH, and mapped the approximate deletion breakpoints to the edges of the flanking SDs using a custom-designed high-density oligonucleotide microarray. Bioinformatic analysis localized 12 of the 25 genes within the microdeletion to nodes in one interaction network. We performed phenotype analyses and found no striking features that distinguish patients with the 16p11.2 microdeletion as a distinct autism subtype. Our work reports the first frequency, breakpoint, bioinformatic and phenotypic analyses of a de novo 16p11.2 microdeletion that represents one of the most common recurrent genomic disorders associated with autism to date.