Monday, April 16, 2007

Sad Hokie

This Hokie is sad, not because he has been forced to wear a Georgia Tech baseball cap by a snarky traveling blogger, but because over 30 fellow Hokies have been senselessly killed.

Here in neighboring Maryland, yesterday's tragedy at Virginia Tech touches nearly everyone I know. We have all made headcounts and phonecalls and e-mails to be sure that our friends and family are still among us.

It becomes a bizarre version of the Kevin Bacon game as people check on those they know. In my circle there are:
  • The friend of a coworker's girlfriend that lived in the dorm where the massacre started.
  • The engineering student that is the older sister of my son's rocket club teammate.
  • The daughter of my wife's former aide that works nights and weekends to afford her kid's out-of-state tuition.
  • The son of my old boss folowing in the footsteps of his alumnus dad.
In a year or two it could be my son, or one of his friends.

We seem to be getting increasingly frequent warnings that complete strangers have too much say over whether we live or die. They strike randomly and unexpectedly. A few years ago I spent an afternoon in a park in Oklahoma City little kids used to play while their parents worked. My uncle spent an entire day covered in concrete dust as he made his way home after fleeing the World Trade Center. My wife has the rules posted in her classroom for what to do if another madman hiding in a car trunk decides schoolkids are fair game.

We are all but a stolen or borrowed gun and a few cents worth of ammunition away from where those Virginia Tech students and teachers and employees are now.

Can we know what drives men to take a gun or a truck or a plane and kill complete strangers?
Never for certain.

Can we make laws or teach classes that will stop these destructive bouts of insanity?
I doubt it.

Can we pray for the victims of these madmen that value their petty grudges or vengeful wishes over the lives of their fellow humans?
We must.


Jenny G said...

FWIW, your sons odds of being killed at college by a sniper are minuscule. As are your odds of being killed by a terrorist. There are many things that you CAN affect, that will have far more influence on your longevity, and your son's. For example, obesity, smoking, lack of exercise, driving drunk or without a seat belt. You are at far more risk from any of these. They don't seem as scary, because there's not tons of sensationalistic television coverage of any of them, but trust me, they are far more dangerous than snipers. And, unlike snipers, there's a lot you can do to lessen the danger they present.

Personally, I find this comforting.

Mooselet said...

It's precisely because we have no control over the whims of complete lunatics that makes it all so scary. You'll never stop someone who is truly intent on causing as much destruction and death as possible before ending their own lives, but something needs to be done to make it harder. The first thing we can do is begin to respect and embrace each other. Aussies call it 'mateship', and it would do Americans a lot of good to embrace it in a wider, country-wide sense and not just when tragedy strikes.

concerned heart said...

We need to look at what happened in the case of the madman to find out what caused his deranged nature. I would suggest looking at what is known to cause his symptoms of muteness, coldness, and inhumanity. Look at how he was described as a child. The smoking gun in this situation that is avoided in the discussion of this tragedy is the role that an older father has in the creation of abnormal offspring. The gunman's father was 38 or 39 years old at the birth of his son. All people should learn the truth about the male biological clock in honor of the Hoakies who died,or were injured etc.
Lunatics like Cho do not come from the ether and more and more men are fathering past the age of

Schizophrenia Risk and the Paternal Germ Line
By Dolores Malaspina

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.

Biological plausibility
We 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 schizophrenia
A 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).