Tag Archives: Rate of de novo mutations and the importance of father’s age to disease risk

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

Citation:

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

Citation:

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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ABSTRACT
ABSTRACT | METHODS | RESULTS | DISCUSSION | CONCLUSIONS | ARTICLE INFORMATION | REFERENCES
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.
http://www.today.com/moms/conversation-were-not-having-about-dads-biological-clocks-2D12184290

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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Father’s age may be linked to Autism and Schizophrenia

26 Aug

In Autism and children of color, moi said:

The number of children with autism appears to be growing. The Centers for Disease Control and Prevention provides statistics on the number of children with autism in the section Data and Statistics:

Prevalence

  • It is estimated that between 1 in 80 and 1 in 240 with an average of 1 in 110 children in the United States have an ASD. [Read article]
  • ASDs are reported to occur in all racial, ethnic, and socioeconomic groups, yet are on average 4 to 5 times more likely to occur in boys than in girls.  However, we need more information on some less studied populations and regions around the world. [Read article]
  • Studies in Asia, Europe, and North America have identified individuals with an ASD with an approximate prevalence of 0.6% to over 1%. A recent study in South Korea reported a prevalence of 2.6%. [Data table ]
  • Approximately 13% of children have a developmental disability, ranging from mild disabilities such as speech and language impairments to serious developmental disabilities, such as intellectual disabilities, cerebral palsy, and autism.  [Read article] http://www.cdc.gov/ncbddd/autism/data.html

In order for children with autism to reach their full potential there must be early diagnosis and treatment.

The National Institute of Neurological Disorders and Stroke has an autism fact sheet:

What is autism?

Autism spectrum disorder (ASD) is a range of complex neurodevelopment disorders, characterized by social impairments, communication difficulties, and restricted, repetitive, and stereotyped patterns of behavior.  Autistic disorder, sometimes called autism or classical ASD, is the most severe form of ASD, while other conditions along the spectrum include a milder form known as Asperger syndrome, and childhood disintegrative disorder and pervasive developmental disorder not otherwise specified (usually referred to as PDD-NOS).  Although ASD varies significantly in character and severity, it occurs in all ethnic and socioeconomic groups and affects every age group.  Experts estimate that six children out of every 1,000 will have an ASD.  Males are four times more likely to have an ASD than females.

What are some common signs of autism?

The hallmark feature of ASD is impaired social interaction.  As early as infancy, a baby with ASD may be unresponsive to people or focus intently on one item to the exclusion of others for long periods of time.  A child with ASD may appear to develop normally and then withdraw and become indifferent to social engagement.

Children with an ASD may fail to respond to their names and often avoid eye contact with other people.  They have difficulty interpreting what others are thinking or feeling because they can’t understand social cues, such as tone of voice or facial expressions, and don’t watch other people’s faces for clues about appropriate behavior.  They lack empathy.

Many children with an ASD engage in repetitive movements such as rocking and twirling, or in self-abusive behavior such as biting or head-banging.  They also tend to start speaking later than other children and may refer to themselves by name instead of “I” or “me.”  Children with an ASD don’t know how to play interactively with other children.  Some speak in a sing-song voice about a narrow range of favorite topics, with little regard for the interests of the person to whom they are speaking.

Children with characteristics of an ASD may have co-occurring conditions, including Fragile X syndrome (which causes mental retardation), tuberous sclerosis, epileptic seizures, Tourette syndrome, learning disabilities, and attention deficit disorder.  About 20 to 30 percent of children with an ASD develop epilepsy by the time they reach adulthood. .

How is autism diagnosed?

ASD varies widely in severity and symptoms and may go unrecognized, especially in mildly affected children or when it is masked by more debilitating handicaps.  Very early indicators that require evaluation by an expert include:

  • no babbling or pointing by age 1
  • no single words by 16 months or two-word phrases by age 2
  • no response to name
  • loss of language or social skills
  • poor eye contact
  • excessive lining up of toys or objects
  • no smiling or social responsiveness.

Later indicators include:

  • impaired ability to make friends with peers
  • impaired ability to initiate or sustain a conversation with others
  • absence or impairment of imaginative and social play
  • stereotyped, repetitive, or unusual use of language
  • restricted patterns of interest that are abnormal in intensity or focus
  • preoccupation with certain objects or subjects
  • inflexible adherence to specific routines or rituals.

Health care providers will often use a questionnaire or other screening instrument to gather information about a child’s development and behavior.  Some screening instruments rely solely on parent observations, while others rely on a combination of parent and doctor observations.  If screening instruments indicate the possibility of an ASD, a more comprehensive evaluation is usually indicated….

What causes autism?

Scientists aren’t certain about what causes ASD, but it’s likely that both genetics and environment play a role.  Researchers have identified a number of genes associated with the disorder.  Studies of people with ASD have found irregularities in several regions of the brain.  Other studies suggest that people with ASD have abnormal levels of serotonin or other neurotransmitters in the brain.  These abnormalities suggest that ASD could result from the disruption of normal brain development early in fetal development caused by defects in genes that control brain growth and that regulate how brain cells communicate with each other, possibly due to the influence of environmental factors on gene function.  While these findings are intriguing, they are preliminary and require further study.  The theory that parental practices are responsible for ASD has long been disproved….https://drwilda.wordpress.com/2012/03/27/autism-and-children-of-color/

Scientists are researching risk factors for autism.

Benedict Carey reports 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

Citation:

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

Abstract

Article tools

Parents must pay attention to whether their children are developing within the parameters of what is appropriate for the child’s age.

Resources:

For more information on neurological disorders or research programs funded by the National Institute of Neurological Disorders and Stroke, contact the Institute’s Brain Resources and Information Network (BRAIN) at:

BRAIN
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Association for Science in Autism Treatment
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http://www.autcom.org
Autism Network International (ANI)
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Tel: 866-366-3361
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Tel: 646-723-3978
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Tel: 301-657-0881 800-3AUTISM (328-8476)
Fax: 301-657-0869
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Tel: 212-252-8584 California: 310-230-3568
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Tel: 407-895-0802
MAAP Services for Autism, Asperger Syndrome, and PDD
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Crown Point, IN   46308
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Tel: 219-662-1311
Fax: 219-662-1315		 National Dissemination Center for Children with Disabilities
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Fax: 202-884-8441
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Tel: 301-496-5133
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Tel: 919-541-3345		 National Institute of Mental Health (NIMH)
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nimhinfo@nih.gov
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Tel: 301-443-4513/866-415-8051 301-443-8431 (TTY)
Fax: 301-443-4279

“Autism Fact Sheet,” NINDS. Publication date September 2009.

NIH Publication No. 09-1877

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