If schizophrenia is simply harmful, if it offers no benefits for survival, how has it persisted over generations? This question is especially puzzling since sufferers have severe problems in social functioning and tend to produce relatively few children.
A partial answer is emerging in new genetics research. A letter just posted in advance of publication in Nature Genetics confirms and expands on some of the findings I reported on recently about random mutations and mental illness. The new research — conducted by Maria Karayiorgou at Columbia University but carried out with Afrikaners in South Africa — looked at people with schizophrenia who come from families with no history of the disease. The patients had a high rate of a particular type of genetic anomaly, copy number (or CN) mutations. Their genes might be normal, but there were too many or too few of them.
In a number of cases, the copy variations were in genes already thought to be linked to schizophrenia. For various other reasons, the researchers believe that the mutations are causal, that they have a major role in producing the severe mental illness.
Some, perhaps most, cases of schizophrenia are familial. But in this population of patients representing “sporadic” cases, most of the CN mutations were not inherited but had arisen “de novo” in the patient with schizophrenia. In other words, any liability to mental illness was not inherited but had occurred in the development of the egg or sperm, or during early maturation. On the other hand, some CN mutations were inherited, suggesting that such abnormalities can be passed on. CN mutations have now been implicated in a number of disorders, including Parkinson's and Alzheimer's diseases, autism, and certain cancers.
This mechanism for producing schizophrenia may not be common. But the new finding suggests one reason mental illnesses might remain prevalent even when they confer an evolutionary disadvantage. They can be created anew in each generation, though mutations.
Also, the research helps explain why no one has found a unique gene for schizophrenia. Normal genes can help cause the disease, if they exist in the wrong number. And a few different genes showed the copy number variations, so genetic defects at various sites seem to contribute to schizophrenia. Since some of the mutations are passed on, familial schizophrenia is likely to prove diverse in this way as well.
This new research presents substantial problems for the “myth of mental illness” argument. We can see why scientists have not discovered a single gene for the disease. It has varied causes — and some are in areas that science could not reach until just now. (The link between epigenetics and mental illness may turn out to have similar implications.) At the same time, the genetic basis for schizophrenia is becoming increasingly apparent.
Like depression, schizophrenia has been subject to romanticization, for example in R. D. Laing’s suggestion that the disorder arises in response to “double binds” in dysfunctional families. This formulation is appealing, but it may simply be wrong; if it is, it may have led to misguided forms of psychotherapy. The question is not what we would prefer to believe, but what we must know in order to help people in pain.
Very likely there are environmental contributors to schizophrenia, including social ones. But inheritance may turn out to play a predominant role. In a press interview, Karayiorgou has expressed hope that exploration of the genes implicated in her studies will lead to guidance regarding treatment and prognosis. Before that, the findings may allow for early diagnosis, using markers no one had imagined until recently.
Persistence of Schizophrenia
Much de novo, non-familial schizophrenia is due to increased paternal age past the age of 32. That is why schizophrenia and its close cousin autism is persistent in the population.
http://www.schizophreniaforum.org/for/curr/Malaspina/default.asp
Schizophrenia Risk and the Paternal Germ Line
By Dolores Malaspina
Paternal age at conception is a robust risk factor for schizophrenia. Possible mechanisms include de novo point mutations or defective epigenetic regulation of paternal genes. The predisposing genetic events appear to occur probabilistically (stochastically) in proportion to advancing paternal age, but might also be induced by toxic exposures, nutritional deficiencies, suboptimal DNA repair enzymes, or other factors that influence the
fidelity of genetic information in the constantly replicating male germ line. We propose that de novo genetic alterations in the paternal germ line cause an independent and common variant of schizophrenia.
Seminal findings
We initially examined the relationship between paternal age and the risk for schizophrenia because it is well established that paternal age is the major source of de novo mutations in the human population, and most schizophrenia cases have no family history of psychosis. In 2001, we demonstrated a monotonic increase in the risk of schizophrenia as paternal age advanced in the rich database of the Jerusalem Perinatal Cohort. Compared with the offspring of fathers aged 20-24 years, in well-controlled analyses, each decade of paternal age multiplied the risk for schizophrenia by 1.4 (95 percent confidence interval: 1.2-1.7), so that the relative risk (RR) for offspring of fathers aged 45+ was 3.0 (1.6-5.5), with 1/46 of these offspring developing schizophrenia. There were no comparable maternal age effects (Malaspina et al., 2001).
Epidemiological evidence
This finding has now been replicated in numerous cohorts from diverse populations (Sipos et al., 2004; El-Saadi et al., 2004; Zammit et al., 2003; Byrne et al., 2003; Dalman and Allenbeck, 2002; Brown et al., 2002; Tsuchiya et al., 2005). By and large, each study shows a tripling of the risk for schizophrenia for the offspring of the oldest group of fathers, in comparison to the risk in a reference group of younger fathers. There is also a "dosage effect" of increasing paternal age; risk is roughly doubled for the offspring of men in their forties and is tripled for paternal age >50 years. These studies are methodologically sound, and most of them have employed prospective exposure data and validated psychiatric diagnoses. Together they demonstrate that the paternal age effect is not explained by other factors, including family history, maternal age, parental education and social ability, family social integration, social class, birth order, birth weight, and birth complications. Furthermore, the paternal age effect is specific for schizophrenia versus other adult onset psychiatric disorders. This is not the case for any other known schizophrenia risk factor, including many of the putative susceptibility genes (Craddock et al., 2006).
There have been no failures to replicate the paternal age effect, nor its approximate magnitude, in any adequately powered study. The data support the hypothesis that paternal age increases schizophrenia risk through a de novo genetic mechanism. The remarkable uniformity of the results across different cultures lends further coherence to the conclusion that this robust relationship is likely to reflect an innate human biological phenomenon that progresses over aging in the male germ line, which is independent of regional environmental, infectious, or other routes.
Indeed, the consistency of these data is unparalleled in schizophrenia research, with the exception of the increase in risk to the relatives of schizophrenia probands (i.e., 10 percent for a sibling). Yet, while having an affected first-degree relative confers a relatively higher risk for illness than having a father >50 years (~10 percent versus ~2 percent), paternal age explains a far greater portion of the population attributable risk for schizophrenia. This is because a family history is infrequent among schizophrenia cases, whereas paternal age explained 26.6 percent of the schizophrenia cases in our Jerusalem cohort. If we had only considered the risk in the cases with paternal age >30 years, our risk would be equivalent to that reported by Sipos et al. (2004) in the Swedish study (15.5 percent). When paternal ages >25 years are considered, the calculated risk is much higher. Although the increment in risk for fathers age 26 through 30 years is small (~14 percent), this group is very large, which accounts for the magnitude of their contribution to the overall risk. The actual percentage of cases with paternal germ line-derived schizophrenia in a given population will depend on the demographics of paternal childbearing age, among other factors. With an upswing in paternal age, these cases would be expected to become more prevalent.....