Father's Age and Serious Mental Illness

I have recently been corresponding with a reader concerning paternal age and schizophrenia. Schizophrenia is a serious mental illness where the individual suffers from delusions and hallucinations. Thought processes are often disturbed. (It is not a "split personality.") Schizophrenia is widely considered to be a neurobiological disorder, caused by a combination of genetics, the prenatal environment, and environmental stressors.

Surprisingly, the New York Times, which is becoming my favorite psychological journal, also devoted an article to the issue, entitled, It Seems the Fertility Clock Ticks for Men, Too. The article summarizes research on the relationship between the father's age and the risk of birth defects:

Geneticists have been aware for decades that the risk of certain rare birth defects increases with the father’s age. One of the most studied of these conditions is a form of dwarfism called achondroplasia, but the list also includes neurofibromatosis, the connective-tissues disorder Marfan syndrome, skull and facial abnormalities like Apert syndrome, and many other diseases and abnormalities.

“We have counseled for quite a long time that as paternal age increases, there is an increased frequency in new mutations,” said Dr. Joe Leigh Simpson, president-elect of the American College of Medical Genetics.

Both autism and schizophrenia have been tied to paternal age, dating back to research published in 2001. In an interview with Medscape, Dr. Dolores Malaspina described her research, also cited in the New Y0rk Times article. (Also check here, here, and here.) Malaspina and her colleagues performed several large-scale studies of demographic data collected in Israel both through the public health system and the Israeli Army. She stated:

We found that paternal age explained over a quarter of the risk for schizophrenia in the population. At the time, people were skeptical. But the findings have been replicated many times now, and not a single study has failed to find this strong relationship between father's age and the risk for schizophrenia. And at this point, other explanations for the relationship have been ruled out, including social factors in the family, prenatal care, and parental psychiatric ailments. There simply seems to be a relationship between paternal age and schizophrenia risk.

Malaspina described the proposed mechanism for this risk:

When Penrose found that paternal age predicted new human genetic diseases, he proposed the Copy Error Theory. He said that each time the spermatozoa are copied there's an opportunity for a new mutation. Sperm cells divide every 16 days after puberty, so the DNA in the sperm of a 20-year-old father has been copied 100 times, but sperm DNA from a 50-year-old father has been copied more than 800 times.

Think of sperm replication as a copy machine. Each time the a copier makes a copy, slight imperfections are created. If you copy the original each time, you never notice a change. But, if you make a copy of a copy, of a copy, of a copy, ad nauseum, you get the familiar spots, streaks, and fading. Human sperm is created from copies of previous generations of sperm, not from copies of an original template in the individual. The DNA in the sperm of a 20 year old has been copied 100 times, while the sperm DNA from a 50 year old has been copied more than 800 times.

Evolutionarily, this is advantageous because it provides for more variation in the offspring. But, with increased variation, comes the risk of negative, as well as positive, traits being transmitted. These include mental retardation and mental illnesses, notably schizophrenia and autism.

The Times cites critics of this research who argue the truism that correlation does not prove causality. That argument is certainly true, but there is more to the research than just correlation:

First, it is also a truism that, to show a cause and effect relationship, the cause must precede the effect. In the case of paternal age that is certainly the case. Paternal age obviously precedes conception.

Second, other explanations must be ruled out. Malaspina and her colleagues controlled for a number of environmental variables, including an adverse fetal environment, maternal age, and psychosocial stressors. Of course, we can never rule out all possible explanations, so we can only rely on a preponderance of evidence. But overall, the evidence favors paternal age.

Third, to argue causality, there must be a plausible mechanism moving from cause to effect. Copy error theory is certainly plausible. It is consistent with known biological processes.

Finally, to argue for causality, there has to be a convergence of data which is consistent with the explanation. Malaspina presents the following data:

1. The risk of schizophrenia rises with age, from .007% for fathers under 25; to 1% for fathers 30 -35, and 2-3 % for fathers 50 and older;
2. The risk factors are consistent across world cultures;
   
3. It's consistent with the data on other genetic diseases, as I mentioned above; and
4. Inbred mice show increasing behavioral disturbances with increasing paternal age.

All of this said, it is important to note that increased paternal age increases risk of schizophrenia, autism, and other genetic diseases, but there are other causes as well. Advanced paternal age is neither necessary nor sufficient for the development of schizophrenia. It is a significant risk factor, and one that can be avoided.

Malaspina argues against warning older men away from having children:

I would personally not discourage anyone from having a child at any age. People weigh their own risks. For the offspring of older fathers, the risk of schizophrenia is about 3%. That means that 97% of the offspring do not have schizophrenia. Other cognitive diseases linked to paternal age include mental retardation of unknown etiology and Alzheimer's disease, and there is a strong relationship between paternal age and autism.

I'm not sure I would completely agree with her. Given this data, I would urge an older man to think twice about parenthood, as I would urge an older woman to think twice. Having a family member with schizophrenia, autism, mental retardation, or other disorder can be a terrible burden for both parents and siblings.

According to one study, about a third of patients with schizophrenia make a full recovery. About one third make a partial recovery, where medication works effectively to manage their symptoms. The remaining one third remain very seriously ill. So, the risks of having an impaired child are small, but the cost can be tremendous, and should not be taken lightly.