Why is the Paternal Age Effect and Genetic Disorders Kept Out of the Public Mind

Why are the wealthy corporate monied families in America funding the research at genome labs?
http://www.hemophiliatoday.co.cc/why-are-the-wealthy-corporate-monied-families-in-america-funding-the-research-at-genome-labs/
Alex asked: Are genetic disease and disorders caused by older paternal age and will there never be cures or for Alzheimer’s, diabetes, MS, hemophilia, autism, schizophrenia,cancers because in non-familial cases they are basic degradations of the human genome caused by genetic copy number variations?

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IN QUESTION Abnormal gene expression may be tied to in vitro techniques.

Picture Emerging on Genetic Risks of IVF

IN QUESTION Abnormal gene expression may be tied to in vitro techniques.


By GINA KOLATA
Published: February 16, 2009
Over the past 30 years, in vitro fertilization has been reassuringly safe. Millions of healthy children have been born and developed normally. And the first IVF baby, Louise Brown, born in England on July 25, 1978, now has her own child, 2-year-old Cameron, conceived without the technique.
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Health Guide: In Vitro Fertilization IVF
But researchers have always wondered whether there might be subtle changes in an embryo that is grown for several days in a petri dish, as IVF embryos are — and, if so, whether would there be any consequences.
Now, with new epidemiological studies and new techniques that allow scientists to probe the genes of embryo cells, some tentative answers are starting to emerge.
The issues have nothing to do with the chances that a woman will have twins, triplets or even, as just happened in California, octuplets. Instead, they involve questions of whether there are changes in gene expression or in developmental patterns, which may or may not be obvious at birth.
For example, some studies indicate that there may be some abnormal patterns of gene expression associated with IVF and a possible increase in rare but devastating genetic disorders that appear to be directly linked to those unusual gene expression patterns. There also appears to be an increased risk of premature birth and of babies with low birth weight for their gestational age.
In November, the Centers for Disease Control and Prevention published a paper reporting that babies conceived with IVF, or with a technique in which sperm are injected directly into eggs, have a slightly increased risk of several birth defects, including a hole between the two chambers of the heart, a cleft lip or palate, an improperly developed esophagus and a malformed rectum. The study involved 9,584 babies with birth defects and 4,792 babies without. Among the mothers of babies without birth defects, 1.1 percent had used IVF or related methods, compared with 2.4 percent of mothers of babies with birth defects.
The findings are considered preliminary, and researchers say they believe IVF does not carry excessive risks. There is a 3 percent chance that any given baby will have a birth defect.
But the real question — what is the chance that an IVF baby will have a birth defect? — has not been definitively answered. That would require a large, rigorous study that followed these babies. The C.D.C. study provides comparative risks but not absolute risks.
Yet even though the risks appear to be small, researchers who are studying the molecular biology of embryos grown in petri dishes say they would like a better understanding of what happens, so they can improve the procedure and allow couples to make more informed decisions.
“There is a growing consensus in the clinical community that there are risks,” said Richard M. Schultz, associate dean for the natural sciences at the University of Pennsylvania. “It is now incumbent on us to figure out what are the risks and whether we can do things to minimize the risks.”
And although the questions are well known, the discussion has been largely confined to scientists, said Dr. Elizabeth Ginsburg, president of the Society for Assisted Reproductive Technology.
Dr. Ginsburg, who is the medical director of in vitro fertilization at Brigham and Women’s Hospital in Boston, says her center’s consent forms mention that there might be an increased risk for certain rare genetic disorders. But, she says, none of her patients have been dissuaded.
Richard G. Rawlins, who directs the in vitro fertilization and assisted reproduction laboratories at the Rush Centers for Advanced Reproductive Care in Chicago, said that when he spoke to patients he never heard questions about growing embryos in the laboratory and the possible consequences.
“I have never had a patient ask me anything” about it, he said, adding, “For that matter, not many doctors have ever asked, either.”
Dr. Andrew Feinberg, a professor of medicine and genetics at Johns Hopkins, became concerned about the lack of information about IVF eight years ago when he and a colleague, Dr. Michael R. DeBaun, were studying changes in gene expression that can lead to cancer.
Their focus was on children with Beckwith-Wiedemann syndrome, characterized by a 15 percent risk of childhood cancers of the kidney, liver or muscle; an overgrowth of cells in the kidney and other tissues; and other possible abnormalities, among them a large tongue, abdominal-wall defects and low levels of blood sugar in infancy.
The syndrome, Dr. Feinberg and Dr. DeBaun found, was often caused by changes in the expression of a cluster of genes, and those changes also are found in colon and lung cancers. Children with those gene alterations had a 50 percent risk of the childhood cancers. The normal risk is less than 1 in 10,000.
The two investigators recruited children with the disorder, following them and studying them in their clinic. Then, several mothers in the study who had had IVF asked the researchers: Was it possible that the fertility treatments had caused Beckwith-Wiedemann syndrome?
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Autism and Schizophrenia and As Fathers Age on a Populations level

Autism and Schizophrenia and As Fathers Age on a Populations level
at：2009-02-17 08:56:45 Click: 21
Autism and Schizophrenia and As Fathers Age on a Populations levelat：2009-02-04 01:06:45 Click: 23 Schizophrenia Risk and the Paternal Germ LineBy Dolores MalaspinaDolores 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 findingsWe 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 evidenceThis 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. Biological plausibilityWe used several approaches to examine the biological plausibility of paternal age as a risk factor for schizophrenia. First, we established a translational animal model using inbred mice. Previously it had been reported that the offspring of aged male rodents had less spontaneous activity and worse learning capacity than those of mature rodents, despite having no noticeable physical anomalies (Auroux et al., 1983). Our model carefully compared behavioral performance between the progeny of 18-24-month-old sires with that of 4-month-old sires. We replicated Auroux's findings, demonstrating significantly decreased learning in an active avoidance test, less exploration in the open field, and a number of other behavioral decrements in the offspring of older sires (Bradley-Moore et al., 2002). Next, we examined if parental age was related to intelligence in healthy adolescents. We reasoned that if de novo genetic changes can cause schizophrenia, there might be effects of later paternal age on cognitive function, since cognitive problems are intertwined with core aspects of schizophrenia. For this study, we cross-linked data from the Jerusalem birth cohort with the neuropsychological data from the Israeli draft board (Malaspina et al., 2005a). We found that maternal and paternal age had independent effects on IQ scores, each accounting for ~2 percent of the total variance. Older paternal age was exclusively associated with a decrement in nonverbal (performance) intelligence IQ, without effects on verbal ability, suggestive of a specific effect on cognitive processing. In controlled analyses, maternal age showed an inverted U-shaped association with both verbal and performance IQ, suggestive of a generalized effect. 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. A variant of schizophreniaA persistent question is whether the association of paternal age and schizophrenia could be explained by psychiatric problems in the parents that could both hinder their childbearing and be inherited by their offspring. If this were so, then cases with affected parents would have older paternal ages. This has not been demonstrated. To the contrary, we found that paternal age was 4.7 years older for sporadic than familial cases from our research unit at New York State Psychiatric Institute (Malaspina et al., 2002). In addition, epidemiological studies show that advancing paternal age is unrelated to the risk for familial schizophrenia (Byrne et al., 2003; Sipos et al., 2004). For example, Sipos found that each subsequent decade of paternal age increased the RR for sporadic schizophrenia by 1.60 (1.32 to 1.92), with no significant effect for familial cases (RR = 0.91, 0.44 to 1.89). The effect of late paternal age in sporadic cases was impressive. The offspring of the oldest fathers had a 5.85-fold risk for sporadic schizophrenia (Sipos et al., 2004); relative risks over 5.0 are very likely to reflect a true causal relationship (Breslow and Day, 1980). It is possible that the genetic events that occur in the paternal germ line are affecting the same genes that influence the risk in familial cases. However, there is evidence that this is not the case. First, a number of the loci linked to familial schizophrenia are also associated with bipolar disorder (Craddock et al., 2006), whereas advancing paternal age is specific for schizophrenia (Malaspina et al., 2001). Next, a few genetic studies that separately examined familial and sporadic cases found that the "at-risk haplotypes" linked to familial schizophrenia were unassociated with sporadic cases, including dystrobrevin-binding protein (Van Den Bogaert et al., 2003) and neuregulin (Williams et al., 2003). Segregating sporadic cases from the analyses actually strengthened the magnitude of the genetic association in the familial cases, consistent with etiological heterogeneity between familial and sporadic groups. Finally, the phenotype of cases with no family history and later paternal age are distinct from familial cases in many studies. For example, only sporadic cases showed a significant improvement in negative symptoms between a "medication-free" and an "antipsychotic treatment" condition (Malaspina et al., 2000), and sporadic cases have significantly more disruptions in their smooth pursuit eye movement quality than familial cases (Malaspina et al., 1998). A recent study also showed differences between the groups in resting regional cerebral blood flow (rCBF) patterns, in comparison with healthy subjects. The sporadic group of cases had greater hypofrontality, with increased medial temporal lobe activity (frontotemporal imbalance), while the familial group evidenced left lateralized temperoparietal hypoperfusion along with widespread rCBF changes in cortico-striato-thalamo-cortical regions (Malaspina et al., 2005b). Other data linking paternal age with frontal pathology in schizophrenia include a proton magnetic resonance spectroscopy study that demonstrated a significant association between prefrontal cortex neuronal integrity (NAA) and paternal age in sporadic cases only, with no significant NAA decrement in the familial schizophrenia group (Kegeles et al., 2005). These findings support the hypothesis that schizophrenia subgroups may have distinct neural underpinnings and that the important changes in some sporadic (paternal germ line) cases may particularly impact on prefrontal cortical functioning. Genetic mechanismSeveral genetic mechanisms might explain the relationship between paternal age and the risk for schizophrenia (see Malaspina, 2001). It could be due to de novo point mutations arising in one or several schizophrenia susceptibility loci. Paternal age is known to be the principal source of new mutations in mammals, likely explained by the constant cell replication cycles that occur in spermatogenesis (James Crow, 2000). Following puberty, spermatogonia undergo some 23 divisions per year. At ages 20 and 40, a man's germ cell precursors will have undergone about 200 and 660 such divisions, respectively. During a man's life, the spermatogonia are vulnerable to DNA damage, and mutations may accumulate in clones of spermatogonia as men age. In contrast, the numbers of such divisions in female germ cells is usually 24, all but the last occurring during fetal life. Trinucleotide repeat expansions could also underlie the paternal age effect. Repeat expansions have been demonstrated in several neuropsychiatric disorders, including myotonic dystrophy, fragile X syndrome, spinocerebellar ataxias, and Huntington disease. The sex of the transmitting parent is frequently a major factor influencing anticipation, with many disorders showing greater trinucleotide repeat expansion with paternal inheritance (Lindblad and Schalling, 1999; Schols et al., 2004; Duyao et al., 1993). Larger numbers of repeat expansions could be related to chance molecular events during the many cell divisions that occur during spermatogenesis. Later paternal age might confer a risk for schizophrenia if it was associated with errors in the "imprinting" patterns of paternally inherited alleles. Imprinting is a form of gene regulation in which gene expression in the offspring depends on whether the allele was inherited from the male or female parent. Imprinted genes that are only expressed if paternally inherited alleles are reciprocally silenced at the maternal allele, and vice versa. Imprinting occurs during gametogenesis after the methylation patterns from the previous generation are "erased" and new parent of origin specific methylation patterns are established. Errors in erasure or reestablishment of these imprint patterns may lead to defective gene expression profiles in the offspring. The enzymes responsible for methylating DNA are the DNA methyltransferases, or DNMTs. These enzymes methylate cytosine residues in CpG dinucleotides, usually in the promoter region of genes, typically to reduce the expression of the mRNA. The methylation may become inefficient for a variety of reasons; one possibility is reduced DNA methylation activity in spermatogenesis, since DNMT levels diminish as paternal age increases (Benoit and Trasler, 1994; La Salle et al., 2004). Another possible mechanism is that this declining DNMT activity could be epigenetically transmitted to the offspring of older fathers. There are a number of different DNMTs that differ in whether they initiate or sustain methylation, and which are active at different ages and in different tissues. Human imprinted genes have a critical role in the growth of the placenta, fetus, and central nervous system, in behavioral development, and in adult body size. It is an appealing hypothesis that loss of normal imprinting of genes critical to neurodevelopment may play a role in schizophrenia. Indeed, one of the most consistently identified molecular abnormalities in schizophrenia has been theorized to result from abnormal epigenetic mechanisms (Veldic et al., 2004), that is, the reduced GABA and reelin expression in prefrontal GABAergic interneurons. An overexpression of DNMT in these GABAergic interneurons, hypermethylating the reelin and GAD67 promoter regions, might be responsible for reducing their mRNA transcripts and expression levels. These decrements could functionally impair the role of GABAergic interneurons in regulating the activity and firing of pyramidal neurons, thereby causing cognitive dysfunction. Later paternal age could be related to the abnormal regulation or expression of DNMT activity in specific cells. ConclusionThese findings suggest exciting new directions for research into the etiology of schizophrenia. If there is a unitary etiopathology for paternal age-related schizophrenia, then it is likely to be the most common form of the condition in the population and in treatment settings, since genetic linkage and association studies indicate that familial cases are likely to demonstrate significant allelic heterogeneity and varying epistatic effects. Schizophrenia is commonly considered to result from the interplay between genetic susceptibility and environmental exposures, particularly those that occur during fetal development and in adolescence. The data linking paternal age to the risk for schizophrenia indicate that we should expand this event horizon to consider the effects of environmental exposures over the lifespan of the father. The mutational stigmata of an exposure may remain in a spermatogonial cell, and be manifest in the clones of spermatozoa that it will subsequently generate over a man's reproductive life. References:Auroux M. Decrease of learning capacity in offspring with increasing paternal age in the rat. Teratology. 1983 Apr;27(2):141-8. Abstract Benoit G, Trasler JM. Developmental expression of DNA methyltransferase messenger ribonucleic acid, protein, and enzyme activity in the mouse testis. Biol Reprod. 1994 50:1312-9. Abstract Bradley-Moore M, Abner R, Edwards T, Lira J, Lira A, Mullen T, Paul S, Malaspina D, Brunner D, Gingrich JA. Modeling The Effect Of Advanced Paternal Age On Progeny Behavior In Mice. Developmental Psychobiology, abstract, 2002; (41)3, 230. Breslow, N. E. and Day, N. E. (1980). The analysis of case-control data. In Statistical Methods in Cancer Research , Volume 1. Lyon: World Health Organization. Brown AS, Schaefer CA, Wyatt RJ, Begg MD, Goetz R, Bresnahan MA, Harkavy-Friedman J, Gorman JM, Malaspina D, Susser ES. Paternal age and risk of schizophrenia in adult offspring. Am J Psychiatry. 2002 Sep;159(9):1528-33. Abstract Byrne M, Agerbo E, Ewald H, Eaton WW, Mortensen PB. Parental age and risk of schizophrenia: a case-control study. Arch Gen Psychiatry. 2003 Jul;60(7):673-8. Abstract Crow JF (1997). The high spontaneous mutation rate: is it a health risk? Proc Natl Acad Sci USA 94:8380-8386. Craddock N, O'Donovan MC, Owen MJ. Genes for schizophrenia and bipolar disorder? Implications for psychiatric nosology. Schizophr Bull. 2006 Jan;32(1):9-16. Abstract Dalman C, Allebeck P. Paternal age and schizophrenia: further support for an association. Am J Psychiatry. 2002 Sep;159(9):1591-2. Abstract Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M, et al. Trinucleotide repeat length instability and age of onset in Huntington's disease. Nat Genet. 1993 Aug;4(4):387-92. Abstract El-Saadi O, Pedersen CB, McNeil TF, Saha S, Welham J, O'Callaghan E, Cantor-Graae E, Chant D, Mortensen PB, McGrath J. Paternal and maternal age as risk factors for psychosis: findings from Denmark, Sweden and Australia.Schizophr Res. 2004 Apr 1;67(2-3):227-36. Abstract Kegeles LS, Shungu DC, Mao X, Goetz R, Mikell CB, Abi-Dargham A, Laurelle M, Malaspina D. Relationship of age and paternal age to neuronal functional integrity in the prefrontal cortex in schizophrenia determined by proton magnetic resonance spectroscopy. Schizophrenia Bulletin, 31:443; 2005. La Salle S, Mertineit C, Taketo T, Moens PB, Bestor TH, Trasler JM. Windows for sex-specific methylation marked by DNA methyltransferase expression profiles in mouse germ cells. Dev Biol. 2004 268:403-15. Abstract Lindblad K, Schalling M. Expanded repeat sequences and disease. Semin Neurol. 1999;19(3):289-99. Abstract Malaspina D, Friedman JH, Kaufmann C, Bruder G, Amador X, Strauss D, Clark S, Yale S, Lukens E, Thorning H, Goetz R, Gorman J. Psychobiological heterogeneity of familial and sporadic schizophrenia. Biol Psychiatry. 1998 Apr 1;43(7):489-96. Abstract Malaspina D, Goetz RR, Yale S, Berman A, Friedman JH, Tremeau F, Printz D, Amador X, Johnson J, Brown A, Gorman JM. Relation of familial schizophrenia to negative symptoms but not to the deficit syndrome. Am J Psychiatry. 2000 Jun;157(6):994-1003. Abstract Malaspina D, Harlap S, Fennig S, Heiman D, Nahon D, Feldman D, Susser ES. Advancing paternal age and the risk of schizophrenia. Arch Gen Psychiatry. 2001 Apr;58(4):361-7. Abstract Malaspina D. Paternal factors and schizophrenia risk: de novo mutations and imprinting. Schizophr Bull. 2001;27(3):379-93. Review. Abstract Malaspina D, Corcoran C, Fahim C, Berman A, Harkavy-Friedman J, Yale S, Goetz D, Goetz R, Harlap S, Gorman J. Paternal age and sporadic schizophrenia: evidence for de novo mutations. Am J Med Genet. 2002 Apr 8;114(3):299-303. Abstract Malaspina D, Harkavy-Friedman J, Corcoran C, Mujica-Parodi L, Printz D, Gorman JM, Van Heertum R. Resting neural activity distinguishes subgroups of schizophrenia patients. Biol Psychiatry. 2005 (a) Dec 15;56(12):931-7. Abstract Malaspina D, Reichenberg A, Weiser M, Fennig S, Davidson M, Harlap S, Wolitzky R, Rabinowitz J, Susser E, Knobler HY. Paternal age and intelligence: implications for age-related genomic changes in male germ cells. Psychiatr Genet. 2005 (b) Jun;15(2):117-25. Abstract Reichenberg A, Gross R, Weiser M, Bresnahan M, Silverman J, Harlap, Rabinowitz J, Shulman L, Malaspina D, Lubin G, Knobler HY, Davidson M, Susser E: Advancing paternal age and Autism. Archives of General Psychiatry. Schols L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004 May;3(5):291-304. Abstract Sipos A, Rasmussen F, Harrison G, Tynelius P, Lewis G, Leon DA, Gunnell D. Paternal age and schizophrenia: a population based cohort study. BMJ. 2004 Nov 6;329(7474):1070. Epub 2004 Oct 22. Abstract Tsuchiya KJ, Takagai S, Kawai M, Matsumoto H, Nakamura K, Minabe Y, Mori N, Takei N. Advanced paternal age associated with an elevated risk for schizophrenia in offspring in a Japanese population. Schizophr Res. 2005 Jul 15;76(2-3):337-42. Epub 2005 Apr 21. Abstract Van Den Bogaert A, Schumacher J, Schulze TG, Otte AC, Ohlraun S, Kovalenko S, Becker T, Freudenberg J, Jonsson EG, Mattila-Evenden M, Sedvall GC, Czerski PM, Kapelski P, Hauser J, Maier W, Rietschel M, Propping P, Nothen MM, Cichon S. The DTNBP1 (dysbindin) gene contributes to schizophrenia, depending on family history of the disease. Am J Hum Genet. 2003 Dec;73(6):1438-43. Abstract Veldic M, Caruncho HJ, Liu WS, Davis J, Satta R, Grayson DR, Guidotti A, Costa E. DNA-methyltransferase 1 mRNA is selectively overexpressed in telencephalic GABAergic interneurons of schizophrenia brains. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):348-53. Abstract Williams NM, Preece A, Spurlock G, Norton N, Williams HJ, Zammit S, O'Donovan MC, Owen MJ. Support for genetic variation in neuregulin 1 and susceptibility to schizophrenia. Mol Psychiatry. 2003 May;8(5):485-7. Abstract Zammit S, Allebeck P, Dalman C, Lundberg I, Hemmingson T, Owen MJ, Lewis G. Paternal age and risk for schizophrenia. Br J Psychiatry. 2003 Nov;183:405-8. Abstract

Men Must Contend With a Biological Clock, Too Older males face higher risk of fathering children with medical problems, research finds ( CNVs)

Men Must Contend With a Biological Clock, Too Older males face higher risk of fathering children with medical problems, research finds
By Kathleen DohenyHealthDay Reporter
SATURDAY, Feb. 14 (HealthDay News) -- It wasn't all that long ago that any suggestion that a man had a "biological clock" like a woman, and should father children sooner rather than later, would have been given short scientific shrift.
Not anymore. Today, a growing body of evidence suggests that as men get older, fertility can and does decline, while the chances of fathering a child with serious birth defects and medical problems increase.
Some studies have linked higher rates of serious health problems such as autism and schizophrenia in children born to men as young as their mid-40s.
And doctors and researchers are busy trying to figure out how men who choose to delay fatherhood -- either by choice or necessity, such as a lack of a partner -- can offset the effects of their biological clocks as those clocks wind down.
Interestingly, problems with reduced fertility can start long before middle age, said Dr. Harry Fisch, one of the pioneers in the field in male fertility and director of the Columbia University College of Physicians and Surgeons' Male Reproductive Center, in New York City.
"We know after age 30, testosterone levels decline about 1 percent per year," said Fisch, author of the book The Male Biological Clock.
Research done at the University of Washington has found that "as men age, DNA damage occurs to their sperm," said Dr. Narendra P. Singh, a research associate professor in the department of bioengineering, who co-authored a study on the subject.
Several other studies point to problems in the offspring of older fathers, as well as older men experiencing fertility problems.
For instance, Fisch and his colleagues found that if a woman and a man were both older than age 35 at the time of conception, the father's age played a significant role in the prevalence of Down syndrome. And this effect was most detectable if the woman was 40 or older -- the incidence of Down syndrome was about 50 percent attributable to the sperm.
Other researchers have found that children born to fathers 45 or older are more likely to have poor social skills, and that children born to men 55 and older are more likely to have bipolar disorder than those born to men 20 to 24 years of age at the time of conception.
On other fronts, researchers at Mount Sinai School of Medicine in New York City found that children of men aged 40 or older were about six times more likely to have autism. Still another study found that the children of fathers who were 50 or older when they were born were almost three times more likely to be diagnosed with schizophrenia....
But Fisch did say, "The sooner, the better."...

Genome Study Points to New Culprit for Schizophrenia

Genome Study Points to New Culprit for Schizophrenia
February 6 (HealthDay News) -- Large, rare structural changes in DNA called copy number variants may play a role in schizophrenia, according to U.S. researchers, who said their findings support a sharp change of direction in genetics research on schizophrenia.

Over the past two decades, researchers have identified dozens of genes and single nucleotide polymorphisms (SNPs or "snips") that could be linked to schizophrenia. But this new study dismisses all of them.

"The literature is replete with dozens of genes and SNPs identified as associated with schizophrenia. But we systematically retested all the leading candidates and concluded that most, if not all of them, are false positives," study lead author Anna Need, a postdoctoral associate at the Center for Human Genome Variation at the Duke Institute for Genome Sciences & Policy, said in a Duke University news release.

Most of the previous studies were too small to properly assess the role of SNPs in schizophrenia, Need said.

She and her colleagues analyzed the genomes of schizophrenia patients and healthy people for SNPs and copy number variants (CNVs). None of the previously identified SNPs appeared significant in schizophrenia, but the researchers identified several CNVs they believe may be associated with the psychiatric disorder.

CNVs are common and usually appear as deletions or duplications of significant stretches of DNA. But the largest deletions -- those over 2 million bases long -- appear only in people with schizophrenia, Need said.

The study was published Feb. 6 in the journal PLoS Genetics.

"What this means is that if we are going to make real headway in assessing genetic links to schizophrenia, we will have to sequence the entire genome of each schizophrenia patient," Need said. "That is a tremendous amount of work, but it is the only way we will be able to find these extremely rare variations."


SOURCE: Duke University, news release, Feb. 5, 2009