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Director’s Blog: Genomics: “The Future is Bright”

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This past month marked the 10th anniversary of the publication of the draft human genome sequence. To mark the occasion, both Science and Nature published a series of special articles. Nature also published a new strategic plan for the National Human Genome Research Institute here at NIH.1 Skeptics listen up – these articles are eye-openers.

Eric Lander in a review in Nature describes progress since the start of the genome project.2 Some of this progress is the result of technical innovation. As Lander says, “The per-base cost of DNA sequencing has plummeted by 100,000-fold over the past decade, far outpacing Moore’s law of technological advance in the semiconductor industry. The current generation of machines can read 250 billion bases in a week, compared to 25,000 in 1990 and 5 million in 2000.”

Some of the progress has altered our understanding of the complexity of the human genome. One extraordinary insight has been the recognition that our DNA contains treasures of information beyond genes – there are several, previously unknown genomic elements that have proven to be important for human biology. And there is an abundance of variation that was never suspected a decade ago.

Some of the progress is health related. At the beginning of this project, fewer than 100 disease-related genes were identified. Today, we know of 2,850 mutations that cause human disease. We have mapped millions of common variants, many of which contribute to individual differences in traits like height and risk for disease. Since 2007, 1,100 genome sites have been implicated in the risk for 165 diseases. For example, 41 common variants are associated with risk for Type 1 diabetes, explaining roughly 60% of the heritability of this disease.

Finally, some of the progress in the past decade can be seen in the changing culture of science, which increasingly shares DNA and clinical information to gather the statistical power for comprehensive genomic analysis.

What has this revolution done for people with mental illness? So far, not much. But the signs of progress are coming fast and furious, with so many new findings just in the past few weeks that one might surmise – to borrow the title of this special issue of Nature – that “the future is bright” for psychiatric genetics as well.

Two examples from last week:

  • NIMH grantee Jonathan Sebat of UC San Diego, and colleagues, traced multiple cases of schizophrenia to a mutation that implicates a single gene – identifying a potential new treatment target. They discovered a duplication of the neuropeptide VIP receptor (VIPR-2) gene, with associated changes detectable in cells from patients with this mutation. While this genetic duplication is a rare event, detected in 29 of 8,290 people with schizophrenia, the finding adds to several other recent reports of deletions or duplications of genomic regions, which appear to cause, perhaps, 4% of schizophrenia cases. Such findings may yield important clues to the mechanisms by which schizophrenia develops – and they begin to suggest that the syndrome “schizophrenia” may actually comprise many different disorders.3
  • A team of researchers led by NIMH grantee Kerry Ressler at Emory University reported discovery of a genetic variation  that may help to explain why women are twice as likely as men to develop post-traumatic stress disorder (PTSD). Studies of PTSD reported a surprising genetic association with genes encoding another neuropeptide– pituitary adenyl cyclase-activating peptide (PACAP) and its receptor PAC-1. Curiously, this association was found only in women, and the risk variant in the PACAP receptor gene was, conspicuously, located at a point that is regulated by estrogen binding. This risk variant was associated with reduced expression of this gene in the brain and in peripheral blood of women but not men with PTSD. Even in the absence of the risk variant, methylation, or epigenetic  regulation, of this gene that reduces expression of PACAP was found in women with PTSD.4

These new findings notwithstanding, it is important to appreciate what genetics will – and will not – do for people with mental illness. Rare “causal” variants, such as the VIPR-2 mutation, can be useful for identifying mechanisms of disease and possibly pointing to pathways for treatment development. Rare variants may identify sub-syndromes, as we have seen in epilepsy and intellectual deficits, but they are not likely to be useful for diagnosing most people with serious mental illness. Common variants, such as the PACAP finding in PTSD may identify risk, but individually they will not explain much of the heritability of mental illness.

We know from equally heritable disorders, like Type 1 diabetes, that (a) many variants are involved, (b) the interaction of these variants (called “epistasis”) may amplify the effects observed from any single finding, and (c) clinically effective medications target variants, even those with only a small contribution to risk, suggesting that other variants may also be useful as medication targets. As an aside, it is notable that none of the many risk genes emerging from whole genome studies of schizophrenia or mood disorders involves the dopamine or serotonin systems, which are the targets of many existing drugs used to treat these disorders.

Most promising for discovering genes for mental illness are the cultural changes in this area of science. Psychiatric geneticists have developed a culture of collaboration and sharing of resources; most have contributed DNA and clinical information to the NIMH Genetics Repository . As a result, there is a treasure trove of over 100,000 samples available for analysis. And scientists from around the world have joined consortia, such as the Psychiatric GWAS Consortium , allowing collaborative analysis of over 10,000 samples from people with schizophrenia. A similar effort for autism is supporting full exome (the protein coding parts of the genome) sequencing in roughly 2,000 DNA samples. None of this would be possible without the participation of patients and their families who have become essential partners in this pioneering research effort.

This broad sharing of DNA and clinical data promises to bring more information about both rare and common variants associated with mental illness. Of course, the endgame is not just the genetic risk architecture of serious mental illness, but a blueprint for where and how the next generation of treatments can be developed. As articles in both Nature and Science note, this vision has been realized already in many areas of medicine during this past decade. It will likely be realized for mental disorders in the decade ahead.

References

1Charting a course for genomic medicine from base pairs to bedside.  Green ED, Guyer MS; National Human Genome Research Institute. Nature. 2011 Feb 10;470(7333):204-13. PMID: 21307933

2Initial impact of the sequencing of the human genome.  Lander ES. Nature. 2011 Feb 10;470(7333):187-97. Review. PMID: 21307931

3Duplications of the neuropeptide receptor gene VIPR2 confer significant risk for schizophrenia.  Vacic V, McCarthy S, Malhotra D, Murray F, Chou HH, Peoples A, Makarov V, Yoon S, Bhandari A, Corominas R, Iakoucheva LM, Krastoshevsky O, Krause V, Larach-Walters V, Welsh DK, Craig D, Kelsoe JR, Gershon ES, Leal SM, Aquila MD, Morris DW, Gill M, Corvin A, Insel PA, McClellan J, King MC, Karayiorgou M, Levy DL, Delisi LE, Sebat J. Nature. 2011 Feb 23. [Epub ahead of print]

4Post-traumatic stress disorder is associated with PACAP and the PAC1 receptor. Ressler KJ, Mercer KB, Bradley B, Jovanovic T, Mahan A, Kerley K, Norrholm SD, Kilaru V, Smith AK, Myers AJ, Ramirez M, Engel A, Hammack SE, Toufexis D, Braas KM, Binder EB, May V. Nature. 2011 Feb 24;470(7335):492-7.
PMID: 21350482