Tag Archives: The conversation we’re not having about dads’ biological clocks

Children of older fathers can have genetic issues: Study reports mental illness risk higher

28 Feb

Apparently there is not an unlimited shelf life for sperm. Benedict Carey reported in the New York Times article, Father’s Age Is Linked to Risk of Autism and Schizophrenia:

Older men are more likely than young ones to father a child who develops autism or schizophrenia, because of random mutations that become more numerous with advancing paternal age, scientists reported on Wednesday, in the first study to quantify the effect as it builds each year. The age of mothers had no bearing on the risk for these disorders, the study found.
Experts said that the finding was hardly reason to forgo fatherhood later in life, though it might have some influence on reproductive decisions. The overall risk to a man in his 40s or older is in the range of 2 percent, at most, and there are other contributing biological factors that are entirely unknown.
But the study, published online in the journal Nature, provides support for the argument that the surging rate of autism diagnoses over recent decades is attributable in part to the increasing average age of fathers, which could account for as many as 20 to 30 percent of cases.
The findings also counter the longstanding assumption that the age of the mother is the most important factor in determining the odds of a child having developmental problems. The risk of chromosomal abnormalities, like Down syndrome, increases for older mothers, but when it comes to some complex developmental and psychiatric problems, the lion’s share of the genetic risk originates in the sperm, not the egg, the study found. Previous studies had strongly suggested as much, including an analysis published in April that found that this risk was higher at age 35 than 25 and crept up with age. The new report quantifies that risk for the first time, calculating how much it accumulates each year.
The research team found that the average child born to a 20-year-old father had 25 random mutations that could be traced to paternal genetic material. The number increased steadily by two mutations a year, reaching 65 mutations for offspring of 40-year-old men.
The average number of mutations coming from the mother’s side was 15, no matter her age, the study found.
“This study provides some of the first solid scientific evidence for a true increase in the condition” of autism, said Dr. Fred R. Volkmar, director of the Child Study Center at the Yale School of Medicine, who was not involved in the research. “It is extremely well done and the sample meticulously characterized.” http://www.nytimes.com/2012/08/23/health/fathers-age-is-linked-to-risk-of-autism-and-schizophrenia.html?emc=eta1


Rate of de novo mutations and the importance of father’s age to disease risk
Journal name: Nature
Volume: 488,
Pages: 471–475
Date published: (23 August 2012)
DOI: doi:10.1038/nature11396
Received 28 February 2012 Accepted 04 July 2012 Published online 22 August 2012
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Carey is updating this study with findings from a newer study.

Benedict Carey reported in the New York Times article, Mental Illness Risk Higher for Children of Older Fathers, Study Finds:

Children born to middle-aged men are more likely than those born to younger fathers to develop any of a range of mental difficulties, including attention deficits, bipolar disorder, autism and schizophrenia, according to the most comprehensive study to date of paternal age and offspring mental health.
In recent years, scientists have debated based on mixed evidence whether a father’s age is linked to his child’s vulnerability to individual disorders like autism and schizophrenia. Some studies have found strong associations, while others have found weak associations or none at all.
The new report, which looked at many mental disorders in Sweden, should inflame the debate, if not settle it, experts said. Men have a biological clock of sorts because of random mutations in sperm over time, the report suggests, and the risks associated with later fatherhood may be higher than previously thought. The findings were published on Wednesday in the journal JAMA Psychiatry.
“This is the best paper I’ve seen on this topic, and it suggests several lines of inquiry into mental illness,” said Dr. Patrick F. Sullivan, a professor of genetics at the University of North Carolina, who was not involved in the research. “But the last thing people should do is read this and say, ‘Oh no, I had a kid at 43, the kid’s doomed.’ The vast majority of kids born to older dads will be just fine.”
Dr. Kenneth S. Kendler, a professor of psychiatry and human molecular genetics at Virginia Commonwealth University, also urged caution in interpreting the results. “This is great work from a scientific perspective,” he said. “But it needs to be replicated, and biomedical science needs to get in gear and figure out what accounts for” the mixed findings of previous studies.
The strengths of the new report are size and rigor. The research team, led by Brian M. D’Onofrio of Indiana University, analyzed medical and public records of about 2.6 million people born in Sweden from 1973 to 2001. Like many European countries, Sweden has centralized medical care and keeps detailed records, so the scientists knew the father’s age for each birth and were able to track each child’s medical history over time, as well as that of siblings and other relatives. Among other things, the analysis compared the mental health of siblings born to the same father and found a clear pattern of increased risk with increasing paternal age.
Compared with the children of young fathers, aged 20 to 24, those born to men age 45 and older had about twice the risk of developing psychosis, the signature symptom of schizophrenia; more than three times the likelihood of receiving a diagnosis of autism; and about 13 times the chance of having a diagnosis of attention deficit disorder. Children born to older fathers also tended to struggle more with academics and substance abuse.
The researchers controlled for every factor they could think of, including parents’ education and income. Older couples tend to be more stable and have more income — both protective factors that help to temper mental problems — and this was the case in the study. But much of the risk associated with paternal age remained. http://www.nytimes.com/2014/02/27/health/mental-illness-risk-higher-for-children-of-older-parents-study-finds.html?_r=0


Original Investigation|February 26, 2014
Paternal Age at Childbearing and Offspring Psychiatric and Academic MorbidityONLINE FIRST
Brian M. D’Onofrio, PhD1; Martin E. Rickert, PhD1; Emma Frans, MSc2; Ralf Kuja-Halkola, MSc2; Catarina Almqvist, MD2,3; Arvid Sjölander, PhD2; Henrik Larsson, PhD2; Paul Lichtenstein, PhD2
[+] Author Affiliations
JAMA Psychiatry. Published online February 26, 2014. doi:10.1001/jamapsychiatry.2013.4525
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Importance Advancing paternal age is associated with increased genetic mutations during spermatogenesis, which research suggests may cause psychiatric morbidity in the offspring. The effects of advancing paternal age at childbearing on offspring morbidity remain unclear, however, because of inconsistent epidemiologic findings and the inability of previous studies to rigorously rule out confounding factors.
Objective To examine the associations between advancing paternal age at childbearing and numerous indexes of offspring morbidity.
Design, Setting, and Participants We performed a population-based cohort study of all individuals born in Sweden in 1973-2001 (N = 2 615 081), with subsets of the data used to predict childhood or adolescent morbidity. We estimated the risk of psychiatric and academic morbidity associated with advancing paternal age using several quasi-experimental designs, including the comparison of differentially exposed siblings, cousins, and first-born cousins.
Exposure Paternal age at childbearing.
Main Outcomes and Measures Psychiatric (autism, attention-deficit/hyperactivity disorder, psychosis, bipolar disorder, suicide attempt, and substance use problem) and academic (failing grades and low educational attainment) morbidity.
Results In the study population, advancing paternal age was associated with increased risk of some psychiatric disorders (eg, autism, psychosis, and bipolar disorders) but decreased risk of the other indexes of morbidity. In contrast, the sibling-comparison analyses indicated that advancing paternal age had a dose-response relationship with every index of morbidity, with the magnitude of the associations being as large or larger than the estimates in the entire population. Compared with offspring born to fathers 20 to 24 years old, offspring of fathers 45 years and older were at heightened risk of autism (hazard ratio [HR] = 3.45; 95% CI, 1.62-7.33), attention-deficit/hyperactivity disorder (HR = 13.13; 95% CI, 6.85-25.16), psychosis (HR = 2.07; 95% CI, 1.35-3.20), bipolar disorder (HR = 24.70; 95% CI, 12.12-50.31), suicide attempts (HR = 2.72; 95% CI, 2.08-3.56), substance use problems (HR = 2.44; 95% CI, 1.98-2.99), failing a grade (odds ratio [OR] = 1.59; 95% CI, 1.37-1.85), and low educational attainment (OR = 1.70; 95% CI, 1.50-1.93) in within-sibling comparisons. Additional analyses using several quasi-experimental designs obtained commensurate results, further strengthening the internal and external validity of the findings.
Conclusions and Relevance Advancing paternal age is associated with increased risk of psychiatric and academic morbidity, with the magnitude of the risks being as large or larger than previous estimates. These findings are consistent with the hypothesis that new genetic mutations that occur during spermatogenesis are causally related to offspring morbidity.

Paul Raeburn posted the article, The conversation we’re not having about dads’ biological clocks at Today’s Moms blog.
According to Raeburn:

Even genetic counselors, who advise couples on such risks, often ignore the risks associated with older fathers, said Jehannine Austin, a genetic counselor at the University of British Columbia whose specialty is psychiatric genetic counseling.
“Medicine tends to focus on the role of mothers in bringing children into the world far more so than we do the role of fathers,” she said. “And I think that really should change.”
Sandra Darilek, an expert on prenatal genetic counseling, says it is still unclear what to do about the risks associated with older fathers.
“There aren’t guidelines about what you should and shouldn’t expect with regard to paternal age,” she said. “Older fathers have a higher risk of passing on what we call new mutations. The problem is that there isn’t any prenatal test that will identify that.”
Furthermore, counselors often do not see couples until the woman is already pregnant, she said. And then it might be wiser not to tell couples about the increased risks associated with fathers’ age. “We’d just be alarming couples when we have nothing to offer them,” she said.
D’Onofrio’s research found that risk increased steadily as fathers aged. There was no age at which the risk zoomed up. Instead, the older the father was, the greater the risk to his children.
“Everyone wants to know when it is safe to have children and when it is not safe,” D’Onofrio said. “There is an increasing risk as men get older. There is not a safe age and a risky age.”
Our two boys are now 7 and 4 — yes, we had another one knowing the risks — and they are fine. We have years to go before we will know for sure whether they have avoided the risks related to my age, but Elizabeth and I have not had any second thoughts about our choices.

Both older males and older females bring genetic issues to any possible late-in-life birth. Potential parents should be advised and counseled concerning these risks.

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