WHO AT AUTISM SPEAKS WILL INFORM THE PUBLIC THAT OLDER PATERNAL AGE PAST 33-35 IS A ROBUST RISK FACTOR FOR AUTISM ON A POPULATION LEVEL?

RAZ GROSS
PRENATAL AND PERINATAL RISK FACTORS FOR AUTISM

A REVIEW and INTEGRATION OF FINDINGS

Alexander Kolevzon, MD; Raz Gross, MD, MPH; Abraham Reichenberg, PhD


Arch Pediatr Adolesc Med. 2007;161:326-333.

The results of this review show that 3 of the 4 population-based studies28-29,32 to examine paternal age reported a significant association with risk of autism and ASDs. The fourth study31 also found that paternal age was older in fathers of case patients with autism compared with fathers of controls, although this relationship was statistically weaker in the adjusted analysis. Thus, advancing paternal age is consistently associated with increased risk of autism and ASDs.
Advanced paternal age has been associated with several congenital disorders, including Apert syndrome,40 craniosynostosis,41 situs inversus,42 syndactyly,43 cleft lip and/or palate,44-45 hydrocephalus,44 neural tube defects,46 and Down syndrome.47 In addition, advanced paternal age has been associated with schizophrenia15 and decreased intellectual capacities in the offspring.48 The most widely proposed mechanism underlying these congenital anomalies is known as the "copy error" hypothesis, first proposed by Penrose.49 After puberty, spermatocytes divide every 16 days, and by the age of 35 years, approximately 540 cell divisions have occurred. As a result, de novo genetic mutations that result from replication errors and defective DNA repair mechanisms are believed to propagate in successive clones of spermatocytes. These mutations accumulate with advancing paternal age and thus help explain how this disorder, which has a large genetic component, can be maintained in the population despite reduced reproduction in affected individuals.


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."

Finally, we examined if paternal age was related to the risk for autism in our cohort. We found very strong effects of advancing paternal age on the risk for autism and related pervasive developmental disorders (Reichenberg et al., in press). Compared to the offspring of fathers aged 30 years or younger, the risk was tripled for offspring of fathers in their forties and was increased fivefold when paternal age was >50 years. Together, these studies provide strong and convergent support for the hypothesis that later paternal age can influence neural functioning. The translational animal model offers the opportunity to identify candidate genes and epigenetic mechanisms that may explain the association of cognitive functioning with advancing paternal age.








Minding Your Mind

New Key to Autism


September 25, 2006


By Michael Craig Miller, M.D.
Harvard Medical School

Convincing Evidence
What Causes These Genetic Errors?
Should Older Men Stop Fathering Babies?
A study published in the September, 2006 issue of the Archives of General Psychiatry may give older prospective fathers pause before plunging into biological parenthood. The authors found a significant increase in the risk of autism and similar disorders as fathers got older.

What Is Autism?
Autism is a profoundly disabling disorder that starts in early childhood. The key features are:

Abnormal social development – little or no eye contact, prefers to be alone
Difficulty communicating – impaired language ability, uses gestures or pointing rather than words
Unusual behavior – spins objects, doesn't like being cuddled
Evidence of strong abilities sometimes in non-verbal areas, such as math or music
Older people with autism may have some ability to interact with people, but about two-thirds are mentally retarded and most cannot live on their own
Unfortunately, the incidence of this illness appears to be on the rise. Some experts think autism is diagnosed more often simply because more people are aware of it. But that's probably not the whole explanation.

Genetic factors almost certainly play a big role. So autism researchers are eager to discover anything that might increase a person's genetic vulnerability, such as delaying parenthood until age 40 or beyond.


The risk was smallest for children of fathers younger than 20 and greatest for children of fathers older than 50. A man in his 40s, for example, was almost 6 times as likely to have an autistic child as a man age 20. This relationship held even after researchers adjusted the results for the year of the person's birth, their socioeconomic status, or the mother’s age.

This is not the first discovery of its type. Healthcare professionals have long known that as parents age, the risk of giving birth to a child with certain illnesses goes up. Older mothers, for example, are more likely to have a child with Down syndrome. In recent years, studies have revealed a link between aging fathers and schizophrenia.

Convincing Evidence

The Archives study took advantage of the extraordinarily complete health records of over 300,000 Israeli men and women who underwent a complete health assessment when they were 17-year olds — draft age. This gave researchers a good way to determine the incidence of autism in the population. The researchers had access to intellectual, medical and psychiatric evaluations of almost all Israeli boys and three-quarters of girls. (Their identities were kept secret, however.) For most individuals, the father’s age at birth was known.



May 2007 PATERNAL AGE AND AUTISM ARE ASSOCIATED IN A FAMILY-BASED SAMPLE

: Mol Psychiatry. 2007 May;12(5):419-421.Paternal age and autism are associated in a family-based sample.Cantor RM, Yoon JL, Furr J, Lajonchere CM.
[1] 1Department of Human Genetics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA [2] 2Department of Pediatrics, David Geffen School of Medicine at University of California at Los Angeles, Los Angeles, CA, USA [3] 3AGRE Consortium, Los Angeles, CA, USA.

PMID: 17453057 [PubMed - as supplied by publisher]


The paternal age distribution of the AGRE fathers, whose first child is autistic differs significantly from that of the 'control' sample (P=0.005). A 2 goodness-of-fit test with 2 degrees of freedom was conducted using percents in the 'control' group age categories to calculate the expected values in the AGRE sample. The shift toward higher paternal ages in those with an affected first-born is seen most dramatically in the group of AGRE fathers who are 30–39 years inclusive, which is 54.7% of the distribution compared with the 41.9 % that is expected. We interpret this shifted age distribution to provide support for the recently reported finding by Reichenberg and co-workers that autism risk is associated with advancing paternal age.
Labels: CM Lajonchere, J Furr, JL Yoon, RM Cantor











Autism Speaks™ Announces New Staff Structure for its Science Program
Organization Restructures Science Program, Announces New Staff Appointments
(NEW YORK, NY – April 16, 2007) – Autism Speaks, a non-profit organization dedicated to increasing awareness of autism and raising money to fund autism research, today announced the re-structuring of its science department. Sophia Colamarino, Ph.D. is named Vice President of Research; Andy Shih, Ph.D. is named Vice President of Scientific Affairs; Clara Lajonchere, Ph.D. is named Vice President of Clinical Programs, and Alycia Halladay, Ph.D. is named Associate Director of Research for Environmental Sciences.

Organizationally the Autism Speaks science program will be divided into 4 primary workgroups. The Etiology Workgroup will focus on the areas of genetics, environmental sciences and epidemiology to gain a better understanding of the causes and susceptibilities involved with autism. The Biology Workgroup will focus on the areas of neuroscience, physiology and molecular biology to gain a better understanding of the pathology and underlying biological mechanisms that generate autism. The Diagnosis Workgroup will focus in the areas of behavioral and biological methods that will lead to better diagnosis and characterization of the autism phenotypes. The Treatment Workgroup will focus on the areas of behavioral, biomedical and technological methods of treatment and intervention services. Autism Speaks will offer a variety of resources and funding mechanisms to support these scientific initiatives and research projects. Funding mechanisms will include Investigator Initiated Grants, High-Risk/High-Impact Awards, and proactive initiatives. In addition, Autism Speaks provides a wealth of research resources, tools, and databanks that help accelerate research within the autism field including AGRE, ATP, ATN, CTN and ISAAC.