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Aging Fathers and Bipolar Children

More Harsh Reality: Aging Fathers and Bipolar Children

By Peter D. Kramer
 
 Like depression, bipolar disorder has been romanticized as an affliction that confers hidden benefits. It may, but evidence is accumulating that suggests manic-depression results from the sorts of genetic disruption that contribute to other severe afflictions, such as schizophrenia and autism.

Readers of this blog may recall that schizophrenia and autism have been linked to “de novo” mutations [1], new abnormal genes that develop in the parent’s sperm line and have not passed a Darwinian, evolutionary test [2] of fitness. The amino acid sequences are simply disrupted. Readers who have looked at yet earlier columns will recall that problems in gene regulation — epigenetic “scarring” [2] — can also give rise to mental illness. Scientists are now suggesting [3] that both of these mechanisms, new mutations and gene dysregulation, may be implicated in bipolar disorder.

More Harsh Reality: Aging Fathers and Bipolar Children

By Peter D. Kramer
 
 Like depression, bipolar disorder has been romanticized as an affliction that confers hidden benefits. It may, but evidence is accumulating that suggests manic-depression results from the sorts of genetic disruption that contribute to other severe afflictions, such as schizophrenia and autism.

Readers of this blog may recall that schizophrenia and autism have been linked to “de novo” mutations [1], new abnormal genes that develop in the parent’s sperm line and have not passed a Darwinian, evolutionary test [2] of fitness. The amino acid sequences are simply disrupted. Readers who have looked at yet earlier columns will recall that problems in gene regulation — epigenetic “scarring” [2] — can also give rise to mental illness. Scientists are now suggesting [3] that both of these mechanisms, new mutations and gene dysregulation, may be implicated in bipolar disorder.

Emma Frans and other researchers at the Karolinska Institute in Stockholm looked at a sample of over seven million Swedes and identified over 13,000 patients who had been hospitalized at least twice for bipolar disorder. The epidemiologists compared these subjects to over 70,000 matched controls. The investigators found that older fathers are more likely (the increase is on the order of 37%) to have offspring with manic depression. Older mothers had more bipolar children, too, but the association was less marked.

More, when the investigators looked at subjects with early-onset bipolarity, the association was very high. Compared with men in their early twenties, men over 55 were more than two-and-a-half times as likely to father a child who would go on be hospitalized for manic depression before age 20.

As with schizophrenia, some manic depression is familial and hereditary, caused in part by genes that have been passed down for generations. Conceivably, as well as doing harm, those genes may confer some adaptive fitness in sufferers or their relatives. Theorists have suggested that high energy and decisiveness, if not frank mania, may be the traits selected for over time. But the association between paternal age and mental illness points in a different direction.

Part of what distinguishes older fathers from older mothers is the nature of the gene line. Women’s eggs go through 23 replications and then are held in the uterus (or expelled) throughout life; the eggs’ genes may deteriorate, but they are much less vulnerable to “gene copy errors.” In contrast, the cells that make sperm have gone through 200 divisions by age 20; by age 40, the number of divisions is up to 660. The sperm of older men is much more likely to have acquired mistakes through faulty replication. On a separate basis, altered genetic regulation in offspring has been related to paternal age. The Karolinska researchers speculate that these two mechanisms may explain why older fathers have more bipolar offspring. Either way, the influence is via “one-off” events, new abnormalities that changes the offsprings’ brain development.

Other interpretations of the data are possible. Perhaps older fathers simply do a worse job of parenting. Here is where the question of early onset comes into play. Early-onset bipolar disorder is more heritable and less related to environmental factors. The fact that manic depression in the teenage years was so much more common in the children of older father speaks toward genetic transmission.

Interestingly, very young (teenaged) fathers also have more children who go on to experience early-onset bipolarity. It may be that “immature sperm” also give rise to de novo genetic disorders; or environment may play a role, via drug and alcohol abuse in the fathers, poor prenatal care on the part of young mothers, epigenetic problems in parents who themselves have been stressed, and then the additional disruption in the early lives of children born to parents who are poor and who (studies show) may demonstrate conduct disorders.

Of course, the association with paternal age proves nothing. It is easy to conjure up epigenetic evolutionary mechanisms that might explain the same data. Perhaps nature has arranged for the sperm of aging parents to be reconfigured to favor manic depression in a sort of “Boy Named Sue” strategy. If the parents may well die early, bipolarity could be a sort of double-or-nothing bet, in which low-level mania gives orphaned offspring a better shot at survival.

But the Karolinska researchers read the results differently. For now, bipolarity is another on a list of mental illnesses that seem to arise from random changes in genes or gene expression — which is to say: syndromes that have long been categorized as mental illness look like just that, expressions of frank biological pathology.
Published on Psychology Today (http://www.psychologytoday.com

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