Men: Your Biological Clocks are Ticking

Men: Your Biological Clocks are Ticking!
by Whitney Rhodes on January 30, 2010

For many years, it was tacitly assumed that while women have a “Sell By” date when it comes to fertility, men become fertile at puberty and remain so until a ripe old age.

Actually, although there is some truth in that myth, to the extent that males do not have a hormonal menopause as women do; the fact is that fertility in men does begin to decline after a certain age.

Men don’t completely stop being fertile at any age.

However, older fathers are prone to problems that younger fathers usually don’t experience.

What are Some of the Problems Experienced by Older Fathers?

A study that was conducted recently at the University of California, Berkeley, on a test group of men aged 22 to 80 showed that the sperm of older men are fewer in number with less mobility, as well as being less able to move in a straight line.

This research also showed an increased risk of achondroplasia, a genetic mutation that produces a kind of dwarfism.

Nor was this the only risk.

Older fathers were shown to have an increased risk of siring children with autism, or who were mentally retarded, or have behavioral problems with conditions such as schizophrenia.

Downs Syndrome, although associated with older mothers, doesn’t seem so far to be one of the risks of older fathers, but testing is still in progress.

It is believed that many times, male fertility problems caused by age and/or a medical condition might be mistaken as a potency issue, and mistakenly treated with a prescription for Viagra or a similar medication.

Investigating male infertility, and research of male sperm is gaining much new ground these days, as specialists recognize that infertility is not any more likely to rest with the female half of a couple than the male.

Today, more than ever, men and women alike are waiting longer to start families. This has given rise to an increasing frequency of fertility problems encountered with older parents.

So, although men are never completely infertile due to age, research has shown that the quality and quantity of sperm decrease with age.

Parental age and birth order in Chinese children with congenital heart disease

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Downloaded from hwmaint.jmg.bmj.com on 30 January 2010
Journal of Medical Genetics, 1982, 19, 441-443
Parental age and birth order in Chinese children with
congenital heart disease
JOHN S H TAY, WILLIAM C L YIP, AND R JOSEPH
From the Department ofPaediatrics, National University of Singapore, Singapore.
SUMMARY Parental age and birth order were studied in 100 Chinese children with congenital
heart disease (proven by cardiac catheterisation) and in 100 controls. A higher incidence of congenital
heart disease was present in the children with higher birth orders. No relationship was
found between the incidence and the paternal or maternal ages. Using the method of multiple
regression analysis this birth order effect was significant (p <0 01) and independent of parental age.
This finding provides indirect evidence of environmental influence in the causation of congenital
heart disease, which is known to be inherited in a multifactorial manner. Family planning to limit
the size of the family may possibly contribute to the reduction of the incidence of congenital heart
disease.
Parental age and birth order effects have been
demonstrated in a number of genetic diseases and
congenital malformations. Certain chromosomal
disorders such as trisomy 21 (Down's syndrome),
trisomy 13 (Patau's syndrome), trisomy 18 (Edwards's
syndrome), and Klinefelter's syndrome have been
shown to be related to maternal age.1 Some autosomal
dominant disorders such as Apert's syndrome,
Marfan's syndrome, and achondroplasia are related
to paternal age.2 A number of congenital malformations
have been shown to be related to birth order.3
Congenital dislocation of the hip and congenital
pyloric stenosis occur more frequently in first born
children, and anencephaly and spina bifida are
more common among first born children as well
as in high birth orders.4
The rationale of studying parental age and birth
order effects is that the results of such studies may
shed some light on pathogenesis. The presence of a
parental age or birth order effect is presumptive
evidence of an environmental influence in the
causation of the disease.' This kind of information
may also be of help in genetic counselling.
The purpose of this study was to investigate the
parental age and birth order effects in Chinese
children with congenital heart disease.
Materials and methods
The material consisted of 100 consecutive Chinese
children with congenital heart disease proven by
Raceived for publication 9 April 1982.
441
cardiac catheterisation. The parental ages (at the
birth of the child) and the birth order of the children
with congenital heart disease were noted. The
parental age and birth order of 100 consecutive
normal Chinese children born in Singapore during
the same period were similarly recorded.
To distinguish the separate effects of paternal age,
maternal age, and birth order, which are usually well
correlated with one another, the method of Smith,5
using multiple regression analysis, was used.
A computer programme was written specially for
the Apple II microcomputer to compute all the
required calculations.
The method and terminology of Smith5 was
followed closely. The essence of this method is that,
given the matrix of the coefficients of regression
(for the controls),
rmm Pmf Pmb
| 1fm Pff Pfb
-Pbm Pbf 13bb
(where 3mf is the coefficient of regression of mother's
age on father's age and so on), it is possible to test
the hypothesis 'that only the father's age has any
appreciable real influence on the condition, the rises
in the mother's age and birth rank being statistical
consequences of this' (as well as similar hypotheses
involving the mother's age and the birth order).5 The
variance-covariance matrix is given by
rt1nrmnImf ltnib
I "'fill 'ff 'Ifh
i bm t/bf t'bb I
Downloaded from hwmaint.jmg.bmj.com on 30 January 2010
442
(where Vmm denotes the variance of m, the maternal
age, in the sample, Umf, the covariance of m and f,
and so on).
The expected rise in the mother's age (and
similarly for the father's age and the birth order) is
3mf Af, where Am is the observed rise in the mother's
age, and the difference between observed and
expected is Am-3mf Af. The error variance of An,
is vmm/n, where n is the number of observations in the
sample, the error variance of Af is uff/n, and their
covariance is /mf /n. Hence, the error variance of
Am-3mf Af iS given by
("imnm 2-2mf",mf 13 Imf!lff)/n.
Smith's method also allows estimation of the
expected independent changes (dm, df, db) in the
variables m, f, and b. The expected increase in the
mean maternal age m owing to dm, df, db is dm+ Pmf
df+rmfdb. By setting this equal to the observed
increase Am, we have
dnm+pmfdf+P3mbdb - Am.
In all, there are three linear equations for the
three unknowns dmi di., and db, which are written
in matrix form ,d- A where d is the column vector
with elements [dmi df, db]T and A similarly is given
by [Am, Af, Ab]T. This has the solution d -1A.
The error variance matrix is given by var d -IV
(I1)T/n.
The values of dm, df, and db are compared with the
size of their respective standard errors to determine
whether there are independent paternal age, maternal
age,'or birth order effects.
Results
The parental ages and birth order of the 100 Chinese
children with congenital heart disease and the 100
controls are shown in table and the correlation
coefficients listed in table 2. The birth order of the
children with congenital heart disease was significantly
higher than the controls (p<0.01), but there
was no significant difference in the paternal and
maternal ages of the patients and controls (p >0 05).
As expected, the parental ages and birth order were
TABLE 1 Parental age and birth order in congenital
heart disease.
Father's AMother's Birth
age (yr) age (yr) order
Congenital heart
disease (n = 100) Mean 31*51 27-66 2.78
SD 6-10 5.41 2-24
Controls (n = 100) Mean 30-37 26-55 2-09
SD 4.52 3.83 1-01
Observed rise in parental age
or birth order 1.14 1.11 0.69
Significance of difference p>0*05 p>0.05 p<0-01
JSHTay, WCL Yip, andR Joseph
TABLE 2 Correlation coefficients.
Congenital Controls
heart disease
Father's age and mother's age 0.7219 0.5809
Father's age and birth order 0.5612 0-4588
Mother's age and birth order 0.4789 0-4696
all well correlated with one another for both groups
of children, with correlation coefficients ranging
from 0 46 to 0 72 (p <0 0001).
The matrix for the regression coefficients (controls)
are shown below:
0000
p = 0.6863
0-1234
0 4916
1*0000
0-1020
1-7871]
2.0628
I.0000 .
The variance-covariance matrix for the children
with congenital heart disease is as follows:
r29 - 2368
v - 23 8014
5*- 8032
23-8014
37- 1817
7-6689
5.8032]
7-6689
5.0218 .
The error variance matrix is given by
r 04195 -0 1029 -0.0760-
vard- -0 1029 0.4188 --0.0451
-0-0760 -- 0 0451 0.0700].
The values of dm,, df, and db, their standard errors,
and the significance of the parental age and birth
order effects are shown in table 3. There was no
significant paternal or maternal age effect (p>0.05)
but the birth order effect was significant (p<0-01).
The various types of congenital heart disease are
shown in table 4.
TABLE 3 Significance ofparental age and birth order
eftects.
Factor acting independently Standard p value
error (SE)
Maternal age- 0.020 (0.03 x SE) 0.648 p>0.05
Paternal age-O0 348 (0.54 x SE) 0*647 p>0.05
Birth order 0 * 730 (2*75 x SE) 0.265 p<0O01
TABLE 4 Types of congenital heart disease.
Diagnosis Number
Ventricular septal defect 22
Fallot's tetralogy 19
Pulmonary stenosis+ventricular or atrial septal defect 11
Persistent ductus arteriosus 8
Transposition of great vessels ±other lesions 8
Endocardial cushion defect 7
Double outlet right ventricle 6
Pulmonary atresia ±ventricular septal defect 5
Pulmonary valvular stenosis 3
Coarctation of aorta + other lesions 3
Others (including Ebstein's anomaly, aorto-pulmonary
window, persistent truncus arteriosus, total
anomalous pulmonary venous drainage, and cor
triatriatum) 8
Total 100
Downloaded from hwmaint.jmg.bmj.com on 30 January 2010
Parental age and birth order in Chinese children with congenital heart disease
Discussion
This is the first study, as far as we are aware, of the
parental age and birth order effects in Chinese
children with congenital heart disease. A moderate
birth order effect is demonstrated.
Nora6 and Nora et a17 demonstrated a multifactorial
inheritance for congenital heart disease.
They showed that the risk of recurrence of a congenital
heart defect in another child in a family
varies with the frequency the lesion is found in the
general population and the type of lesion in the first
affected child, the recurrence risk ranging from about
1 to 4 %. Applying Falconer's model8 for the
estimation of heritability to their data, it can be
shown that the heritability of various types of
congenital heart disease is in the order of 50 to 80 %.
This measure can give some indication of the
relative importance of heredity and environment
in the causation of the disease.
The presence of a birth order effect in congenital
heart disease is indirect evidence of the presence of
an environmental influence in the causation of the
disease and is thus consistent with what is known
about the multifactorial inheritance of congenital
heart disease. While the exact mechanism of the
birth order effect is at present unclear, this finding
may nevertheless have practical applications. The
increase in the incidence of congenital heart disease
with the higher birth orders would suggest that
family planning to reduce the size of families may
possibly contribute towards the lowering of the
incidence of congenital heart disease.
References
Emery AEH. Methodology in medical genetics. An introduction
to statistical methods. Edinburgh, London, New
York: Churchill Livingstone, 1976.
2 Jones KL, Smith DW, Harvey MAS, Hall BD, Quan L.
Older paternal age and fresh gene mutation: data on
additional disorders. J Pediatr 1975;86:84-8.
3 Carter CO. The inheritance of common congenital
malformations. Prog Med Genet 1965 ;4:59-84.
4 Fedrick J. Anencephalus: variation with maternal age,
parity, social class and region in England, Scotland and
Wales. Ann Hum Genet 1970;34:31-8.
5 Smith CAB. Note on the estimation of parental ageeffects.
Ann Hum Genet 1972;35:337-42.
6 Nora JJ. Multifactorial inheritance hypothesis for the
etiology of congenital heart disease. Circulation 1968;38:
604.
7 Nora JJ, Vargo TA, Nora AH, et al. Dexamphetamine:
a possible environmental trigger in cardiovascular malformations.
Lancet 1970;i :1290.
Falconer DS. The inheritance of liability to certain
diseases, estimated from the incidence among relatives.
Ann Hum Genet 1965;29:51-76.
Requests for reprints to Professor John Tay,
University Department of Paediatrics, Singapore
General Hospital, Outram Road, Singapore 0316.

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice.

Eur J Neurosci. 2010 Jan 25. [Epub ahead of print]

Advanced paternal age is associated with alterations in discrete behavioural domains and cortical neuroanatomy of C57BL/6J mice.
Foldi CJ, Eyles DW, McGrath JJ, Burne TH.

Queensland Brain Institute, The University of Queensland, St Lucia, Qld 4072, Australia.

Abstract Advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism and schizophrenia. A previous study in mice suggested that the offspring of aged sires have altered locomotion and avoidance learning. The aim of the current study was to conduct a comprehensive behavioural screen in adult offspring of mice of APA. We also examined brain morphology in neonate and adult mice. The adult offspring of 12- to18-month-old (APA) and 4-month-old (control) male C57BL/6J mice underwent a behavioural test battery comprising tests for locomotion, anxiety, exploration, social behaviour, learned helplessness and sensorimotor gating. The brains of these mice were collected at 3 months and imaged ex vivo using a 16.4T MRI scanner to assess gross neuroanatomy. Neuroanatomy was also examined at birth in a separate cohort of animals. Overall, the APA mouse model was associated with subtle behavioural changes and altered cortical morphology. The behavioural phenotype of female APA mice included increased anxiety-related behaviour, increased exploration and decreased learned helplessness compared to control females. Male APA mice had thinner cortices at birth and increased cortical volume as adults. This animal model may assist in exploring the mechanism of action linking APA with disorders such as schizophrenia and autism.

PMID: 20105239 [PubMed - as supplied by publisher]

Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta.

Journal of Medical Genetics 1986;23:227-230; doi:10.1136/jmg.23.3.227
Copyright © 1986 by the BMJ Publishing Group Ltd.
Risk of dominant mutation in older fathers: evidence from osteogenesis imperfecta.
A D Carothers, S J McAllion, C R Paterson

The mean paternal age at birth of 80 presumed mutant cases of dominant osteogenesis imperfecta (OI) was significantly higher than that of population controls and remained so after adjusting for maternal age. There was also an increase in mean maternal age (not significant) which disappeared after adjusting for paternal age. No significant increase in maternal or paternal age was found in cases having OI either of a dominant type with an affected parent or of a type (Sillence type III) usually regarded as recessive. We conclude that, as in certain other dominant conditions, the risk of mutant OI increases with paternal age. However, the rate of increase of risk with paternal age appears to be considerably lower than, for example, in achondroplasia. The overall risk of fresh dominant mutation in older fathers may therefore be lower than has previously been suggested.

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A discussion about Paternal Age and Health of Children

Will our age gap be something to worry about when we decide to get pregnant?
January 11, 2010 3:57 PM Subscribe
Will our age gap be something to worry about when we decide to get pregnant?


My partner and I, a heterosexual couple, are a decade apart in age, and we expect that this relationship will result in marriage and children. It will be years before I am ready for kids, and I'm concerned that by that time, my partner will be an older-than-average father (I will not be an older mother, due to the age gap), and I've read some research that this could contribute to a higher risk of birth defects.

Is this something we should be seriously concerned with, enough so that I should consider having children sooner? Would it be worth it for our peace of mind to store his sperm now, and forgo natural conception for a more clinical, but less risky conception?
posted by anonymous to health & fitness (25 comments total) 3 users marked this as a favorite

Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects

Ann Epidemiol. 2010 Jan 5. [Epub ahead of print]

Association of Paternal Age and Risk for Major Congenital Anomalies From the National Birth Defects Prevention Study, 1997 to 2004.
Green RF, Devine O, Crider KS, Olney RS, Archer N, Olshan AF, Shapira SK; The National Birth Defects Prevention Study.

National Center on Birth Defects and Developmental Disabilities; Centers for Disease Control and Prevention; Atlanta, GA (R.F.G., O.D., K.S.C., R.S.O., S.K.S.); Texas Department of State Health Services; Austin, TX (N.A.); and Department of Epidemiology; University of North Carolina; Chapel Hill, NC (A.F.O.).

PURPOSE: The objective of this study was to examine the associations between paternal age and birth defects of unknown etiologies while carefully controlling for maternal age. METHODS: By using 1997 to 2004 data from the National Birth Defects Prevention Study, we fit logistic regression models with paternal and maternal age as continuous variables while adjusting for demographic and other factors. RESULTS: Elevated odds ratios (ORs) for each year increase in paternal age were found for cleft palate (OR. 1.02, 95% confidence interval [95% CI], 1.00-1.04), diaphragmatic hernia (OR, 1.04; 95% CI, 1.02-1.06), right ventricular outflow tract obstruction (OR, 1.03; 95% CI, 1.01-1.04), and pulmonary valve stenosis (OR, 1.02, 95% CI, 1.01-1.04). At younger paternal ages, each year increase in paternal age correlated with increased odds of having offspring with encephalocele, cataract, esophageal atresia, anomalous pulmonary venous return, and coarctation of the aorta, but these increased odds were not observed at older paternal ages. The effect of paternal age was modified by maternal age for gastroschisis, omphalocele, spina bifida, all orofacial clefts, and septal heart defects. CONCLUSIONS: Our findings suggest that paternal age may be a risk factor for some multifactorial birth defects. Published by Elsevier Inc.

PMID: 20056435 [PubMed - as supplied by publisher]

Paternal Age and Schizophrenia

Paternal Age and Schizophrenia
Research Date:
03/23/2006
An Expert Interview with Dolores Malaspina, M.D., M.P.H.

Great Neck, NY - March 23, 2006) — Scientists have linked paternal age to genetic diseases since the 1950s, and some have suggested an association between the age of the father and the risk for schizophrenia. In 2001, Dolores Malaspina, M.D., M.P.H., and her colleagues reported their research identifying a relationship between paternal age and the occurrence of schizophrenia. On behalf of Medscape* Jessica Gould interviewed Dr. Malaspina, Professor of Clinical Psychiatry at Columbia University and Research Psychiatrist at New York State Psychiatric Institute in New York City. Dr. Malaspina elaborates on her research and speaks about new directions in genetic research on schizophrenia. (NARSAD NOTE: Dr. Malaspina was a NARSAD 1993 and 1995 Young Investigator and a 2001 Independent Investigator.)

Medscape: Tell me about your research on paternal age and schizophrenia.

Dolores Malaspina: I have been compelled by the idea that schizophrenia is not a single disease. The consensus in the field is that schizophrenia is a syndrome, and a syndrome is a collection of different disorders. Yet there is still some controversy over whether or not there are variants of schizophrenia that might have separate causes and respond differently to various medications.

Since beginning my research in the late 1980s, I have focused on this heterogeneity, and one way that I've done that is by examining aspects of the disease in people who come from densely affected families, where two or more relatives have schizophrenia, and comparing them with cases of schizophrenia that have no family history of any chronic psychosis.

Now, in genetic research, it's known that for human genetic diseases, when a new case presents itself in a family, the mutation almost always arises during spermatogenesis. We have known for almost 100 years that the late born children in a family have more new genetic diseases. In the 1950s, a scientist named Penrose showed that only the age of the father predicts these genetic diseases. Over the last decade, it was shown that the risk for many complex genetic diseases was also correlated with paternal age. I thought that if schizophrenia cases with no family history were due to new genetic events, maybe they would also be correlated with the father's age.

I have the good fortune to be funded by the National Institutes of Health to study a very special birth cohort in Israel of about 100,000 pregnancies. We have a rich amount of demographic and clinical data on the parents, including the age of the father. The analysis showed what we considered to be a striking effect of the age of the father on the risk for schizophrenia.

Medscape: Could you tell me more about this group of research subjects from Israel?

Dr. Malaspina: The offspring were born between 1964 and 1976, and the original birth cohort was designed to examine the health of women during pregnancy as well as fetal outcomes. Israel maintains a high-quality psychiatric case registry. Working with the people at the Ministry of Health in Israel, my colleagues linked the birth cohort data to the psychiatric case registry data. The results showed that the risk of schizophrenia was tripled for the offspring of the oldest group of fathers.

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.

Medscape: Can you explain why the relationship between paternal age and schizophrenia exists?

Dr. Malaspina: 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. By comparison, egg cells from the mother only undergo a few dozen cell divisions all together. It is clear that there are many more opportunities for mutations to occur during spermatogenesis and that these increase with the age of the father. That is why new mutations are introduced in mammals in proportion to paternal age.

To further establish that paternal age is associated with schizophrenia risk, we went back to examine if paternal age is related to other factors associated with schizophrenia risk. We looked at intellectual functioning at age 17 in our birth cohort. Those data were available because adolescents in Israel are screened for military service. Working with personnel at the Israeli Defense Force, we examined whether intelligence was related to paternal age. And what we found was a very strong specific effect of paternal age on performance IQ. Very young mothers and very old mothers had offspring with impairments in verbal and performance intelligence. While there was no effect of late fathers' age on verbal IQ, there was a strong effect on performance intelligence, or nonverbal intelligence, which we have published.

In a parallel study, we examined the effect of late paternal age in a mouse model. Working with my colleague, Jay Gingrich, we studied several cohorts of inbred mice to compare offspring with younger and older fathers. The mouse model demonstrated striking effects of paternal age on the behavior of mice.

Those three lines of evidence provide converging data that paternal age does influence neural functioning and that paternal age is a plausible risk factor for schizophrenia.

Medscape: Could you describe what is meant by sporadic schizophrenia and how that relates to paternal age?

Dr. Malaspina: This goes along with the issue of whether schizophrenia is one single disease or several different variants, several different diseases. If it is several diseases, we could make much more progress if we knew how to separate individuals who have one variant of the disease from individuals who have the other variant, such as for treatment studies.

So, we have this finding that father's age predicts schizophrenia, but we don't know if the genetic changes are in the same genes that cause familial schizophrenia or if they occur at a different place. Some of the birth cohorts have actually looked to see how the risk of schizophrenia with paternal age is related to the family history of schizophrenia. The finding is that father's age is not connected to the risk of schizophrenia when it runs in families, but only for cases with no family history. That is called sporadic schizophrenia.

We have also looked at patients, with the help of funding from the National Alliance for Research on Schizophrenia and Depression, and we have examined whether or not cases with late paternal age and no family history have different symptoms and brain abnormalities from those of other cases. That work is under way.

Medscape: You also looked at the duration of the parents' marriage.

Dr. Malaspina: Yes, and we found that the duration of marriage was protective against the risk for schizophrenia. This goes in the opposite direction of paternal age, but it's an independent factor. Couples that have a very long marriage are less likely to have offspring with schizophrenia. One possibility is that parents who have mental disorders themselves may have shorter marriages. Another possibility is that there is an increased risk of schizophrenia when there is a marital separation.

Medscape: A variety of environmental factors can influence the development of schizophrenia. How do you control for that?

Dr. Malaspina: On the one hand, there may be scores of different intrauterine exposures that increase the risk for schizophrenia through different pathways. Another possibility, though, is that there are only a few final common pathways through which various intrauterine adversities are linked to the risk for schizophrenia.

The Barker hypothesis deals with the area of fetal programming. Research shows that the risk for many adult-onset chronic diseases, such as cardiovascular disease, obesity, diabetes, and hypertension, is related to fetal development. The mechanism may be that an adverse fetal environment compromises the development of organs and tissues and changes lifelong gene expression. The fetus survives, but its health is compromised. Effects on the developing nervous system could contribute to schizophrenia risk. So that's a possible pathway for the risk for schizophrenia, through a variety of prenatal exposures.

The benefit of our study in Israel is that we had such a wealth of obstetric data. The birth cohort involved early pregnancy interviews with the mom. It also involved evaluations of the progress of the pregnancy and records of the delivery. Our study was able to show that other prenatal exposures did not explain the linkage of paternal age to the risk of schizophrenia. Also, there have been many excellent studies after ours was conducted that have looked at numerous fetal exposures and found that those also do not explain the risk of paternal age for schizophrenia.

I do, however, believe that many fetal exposures can increase the risk of schizophrenia. I would suggest that the mechanism of these events may be via changes in lifelong gene expression.

Medscape: What about the influence of environmental factors after birth, during childhood and adolescence?

Dr. Malaspina: I think three of the interesting factors that have been linked to the risk of schizophrenia are severe stress in a stress-sensitive person who has underlying genes for schizophrenia, traumatic brain injury in those with underlying genes for schizophrenia, and, very importantly, cannabis exposure in early adolescence.

Medscape: Your research about paternal age became public in 2001. Do you think fewer men over a certain age might choose to have children as a result?

Dr. Malaspina: I haven't heard that. 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 percent. That means that 97percent 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.

Medscape: What do you expect to be the future of your research in this area?

Dr. Malaspina: The genes for schizophrenia that we have identified lately are very interesting; they explain a large degree of the risk of the disease. Attention probably should turn toward factors that affect the expression of these genes and other genes. This is the area of epigenetics, the code that determines whether or not genes will be expressed.

We're pursuing a gene expression hypothesis for paternal age and schizophrenia. Humans have dozens or hundreds of genes that are expressed, not on the basis of being dominant or recessive, but on the basis of which parent we have inherited them from. So genes that control the growth of the fetus tend to be expressed on the basis of inheritance from the father. Other genes are expressed only on the basis of inheritance from the mother. These are called "parent of origin genes" or "parentally-imprinted genes." In these genes, the father's copy is expressed and the mother's is silenced, or vice versa. We are interested in this mechanism of gene-silencing. For the male parent, the silencing, or the activation/expression of genes from dad, takes place late in spermatogenesis. So our hypothesis and model right now for how paternal age affects the risk for schizophrenia is that it has altered the expression of genes inherited from the father.

Even exposures that interact with genetic susceptibility may act by changing gene expression, such as traumatic brain injury, cannabis, and stress. Maybe we can integrate our understanding of the many exposures tied to schizophrenia and the many genes tied to schizophrenia with the understanding that certain exposures may act by changing gene expression.

Meanwhile, some individuals who develop schizophrenia have a good outcome and stability without much deterioration -- but not as many as we would like. If we can't prevent the disease, perhaps we can learn the risk factors for deterioration and how to prevent it.

Although I see schizophrenia as a syndrome of separate illness variants, I think the field has benefited from considering it as a single disease. From here forwards, we may be diluting our ability to find risk factors and optimize outcome by considering the disease as a whole. To go forward in schizophrenia, we need to better understand how similar symptoms may arise from abnormalities in different neural circuits; that the set of symptoms we call schizophrenia could reflect a common pathway, but that the underlying biology may differ for groups of people, and that those differences may explain which medications they should receive, or which factors are more adverse for them. I think the field needs to move toward a finer understanding of the variants that exist. The identified genes may be clearly explanatory for some cases but not for others.

Funding Information

This interview is published in collaboration with NARSAD: The Mental Health Research Association, and is supported by an educational grant from Pfizer.

Dolores Malaspina, M.D., Professor of Clinical Psychiatry, Columbia University, New York, NY;
Director of Clinical Neurobiology, New York State Psychiatric Institute and Columbia University Medical Center, New York, N.Y.

Disclosure: Jessica Gould has disclosed no relevant financial relationships.

Disclosure: Dolores Malaspina, MD, has disclosed no relevant financial relationships.

*Reprinted with permission from Medscape Psychiatry & Mental Health 2006:11(1) http://www.medscape.com/viewarticle/520009 © 2006, Medscape. Please be advised that Medscape requires free registration to view articles.