NEW YORK – The long era of nonreproducible findings in psychiatric genetics is now over, especially in the areas of autism and schizophrenia, Dr. Matthew W. State reported in a presentation at the annual meeting of the American Psychiatric Association.
Indeed, "these molecular clues ... offer the potential to build our way up from the genome to neurons," Dr. State said. "The question is: What do we do now that we have a clear path?"
According to Dr. State, while gene studies in autism and schizophrenia have both made major progress recently, the findings couldn’t be more different.
That’s because in autism, new studies point to rare, de novo mutations (variations that arise spontaneously and are not present in either parent) that nevertheless carry relatively high risk for the disease – the opposite of what is presumed to be the case in schizophrenia, said Dr. State, a child psychiatrist and human geneticist who serves as chair of the department of psychiatry at the University of California, San Francisco.
For example, he highlighted one study of 928 autism patients, including 200 siblings, which found that the total number of nonsynonymous de novo single nucleotide variants was significantly greater in probands, compared with unaffected siblings (P = .01) (Nature 2012;485;237-41).
Moreover, another recent study offers a list of 10 genes on which rare de novo mutations appear to carry very large risks, possibly contributing to as many as 1% of cases of autism (Science 2012;338:1619-22); a new study identifying 25 more genes is set to be submitted by Dr. State and his colleagues in a few weeks.
On the other hand, the story of genetics in schizophrenia is quite different, with new studies implicating relatively common polymorphisms, each carrying much smaller risks, likely less than 20%.
For example, a recent paper on schizophrenia looking for rare point mutations among 600 trios was not able to show an increased overall rate in cases vs. controls, he said (Nature 2014;506:179-84).
And another meta-analysis of several thousand patients confirmed that somewhere between 6,000 and 10,000 independent, mostly common single nucleotide polymorphisms (SNPs) contribute to the overall risk for schizophrenia; however, odds ratios on each of these SNPs rarely exceed 1.2, said Dr. State (Nat. Genet. 2013;45:1150-9).
But perhaps the most "mind-bending" new finding for both diagnoses is the discovery that single genes and genetic mutations correspond to myriad phenotypes, subphenotypes, and even different diseases entirely.
"Genetic risks are robust and reproducible, but they have not read any version of the DSM," joked Dr. State, former professor of child psychiatry, psychiatry, and genetics at Yale University, New Haven, Conn.
"There has been a hypothesis out there among many that if we just were able to subgroup patients in advance, that this would lead to greater genetic homogeneity, and ... so far there is not much evidence [in autism, specifically] that this strategy adds any additional power to these studies," Dr. State said.
Not only that, but identical genes appear as possible culprits in different conditions.
For instance, the previously mentioned study of 928 autism patients also highlighted two autism probands carrying nonsense de novo mutations on the SCN2A gene, which encodes a sodium channel alpha subunit; the gene previously has been shown to have strong associations with seizure disorders.
In any case, according to Dr. State, almost all of the newest genetic findings in autism and schizophrenia owe their existence to extensive collaborations and genetics databases – for example, the Autism Genetics Resource Exchange, run by the nonprofit Autism Speaks; the Psychiatric Genomics Consortium; and the Autism Sequencing Consortium, which Dr. State coleads.
"There is great progress underway in understanding the biological bases of these conditions because of the involvement of thousands of patients and families willing to participate in research," said Dr. State in an interview. "We should really be shooting for a situation not unlike cancer, in which every patient who is being seen has the opportunity to be in a research study, including a clinical trial."
Indeed, while the present genetic tests considered standard of care for the disease serve mostly to help inform the family about future risks, "This is liable to change in the not-too-distant future as we are better able to correlate known genetic risks with treatment response, course of illness, etc.," he said.
Which leads to the "big question" for autism genetics, and indeed, psychiatric genetics as a whole: "Will there really be any opportunity to intervene?"
The answer, so far, remains unclear. But despite the "flag in the ground about genetic risks" for these conditions, Dr. State emphasized that, as in other medical conditions, "genes provide critical clues to understand what is going on, but in psychiatric conditions, genes are not fate, they predispose," he said. "Genes are not destiny."