Do Fathers Matter?: What Science Is Telling Us About the Parent We've Overlooked (22 page)

This was in the early 1970s, when many psychiatrists believed that schizophrenia was caused by a dominant, overpowering mother who rejected her child. “The prevailing notion was that this was not a biological disorder,” said Malaspina. Further, Eileen’s doctors said, there was no treatment. The damage done by a schizophrenia-inducing mother was irreparable, and the family should “hang crepe”—that is, prepare for a funeral. “There was a sense she would never be well, that we should lock her up and throw away the key.” Malaspina, too, was tortured over whether she’d done something to cause her sister’s illness. “I would replay our childhood over and over again. I’d think about the time I didn’t want her to play with my friends and me, or when she called me once and I hid behind a tree. I spent many years feeling horribly guilty about that, and I’m sure for my mother it was magnified a hundredfold.”

While Eileen was deteriorating, Malaspina continued in college, where she studied environmental biology and then zoology in graduate school. Before finishing her Ph.D., she got married and left graduate school, taking a job at a drug company, where she drifted into research on substances that could alter brain chemistry. She was in the job for a while before she made the connection with her sister. “I was looking at molecules in the lab that might be related to psychosis,” she said. “My sister had very bad psychosis.” Such research was beginning to establish a biological basis for schizophrenia and would ultimately demolish the notion that it was caused by domineering mothers. Malaspina, who’d never accepted the advice about hanging crepe, began to wonder whether it might be possible to find a drug that could help her sister. She quit her job and went to medical school with a single goal in mind—curing schizophrenia.

When she finished medical school and her residency, Malaspina took a research job at Columbia University in New York, where she ran into the first of many puzzles about the disorder. People with schizophrenia, because they often have trouble functioning, are much less likely than others to marry and have children. If people with schizophrenia are not reproducing as much as people without it, the disease should eventually disappear from the population. But it hasn’t; the incidence of schizophrenia in the population has remained constant at about 1 percent. While schizophrenia can run in families, it might come as a surprise to learn that most cases are what are called sporadic—they show up in people with no family history of schizophrenia.

While mothers had long been blamed for causing schizophrenia, the biological approach to the study of disease began to raise questions about fathers. The problem was this: the eggs in a woman’s body age as she does. Even if a woman has children when she’s young, her eggs are already a couple of decades old. It seems logical to wonder whether they deteriorate as she gets older; we know that most of the rest of our body parts get a little ragged with age.

But that’s not quite the way biology works. The time that cells are most susceptible to genetic damage is when they’re dividing. That’s when genes are copied, and they’re not always copied correctly. Mistakes can pop up. That explains why sperm can be more vulnerable than eggs. Because they are being continuously manufactured, genetic copying is going on all the time. So it’s sperm—not eggs—that are most likely to contain genetic errors. Geneticists think it’s that incessant copying and recopying that gives rise to the genetic errors that cause dwarfism, Marfan syndrome, and the other ailments associated with older fathers. Malaspina learned about this when she was in medical school. With her single-minded focus on schizophrenia, she began to wonder whether the recognized potential for genetic errors in fathers’ sperm might be at least partly responsible for schizophrenia.

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At Columbia, Malaspina learned about a unique research opportunity in Israel. During the 1960s and 1970s, all births in and around Jerusalem were recorded, along with information on the infants’ families. And all those children received a battery of medical tests as young adults, because of Israel’s military draft. “All Jewish individuals in the country have to report to the draft board, and there is a mandatory screening for intelligence, psychiatric conditions, medical conditions,” said Abraham Reichenberg, a neuropsychologist at Mount Sinai School of Medicine in New York, who has worked with Malaspina in studies of this population. “It’s done on practically everybody unless they’re out of the country or have died.” Because the records cover an entire population, the data is free from the biases that might creep in if researchers looked at, say, only people who’d graduated from college, or only those who went to see a doctor.

In 2001, Malaspina had looked at the whether the risk of schizophrenia increased in the children of older fathers, and she found that it did. It was the first large-scale study to link sporadic cases of schizophrenia to fathers’ age, and most researchers didn’t believe it. “We were absolutely convinced it was real, but other people didn’t think it was,” Malaspina said. “Everybody thought men who waited to have children must be different.” That is, maybe these older fathers had some of the makings of schizophrenia themselves—not enough for the disease to be recognized, but enough that it took these men a little longer to get settled, married, and have children.

Other groups tried to repeat the study using other populations. In all these studies, researchers took a close look at whether there was anything at all about older fathers, other than their age, that could have increased the risk of schizophrenia in their children. The link with age only became clearer. “That result has been replicated at least seven times,” said Robert K. Heinssen, the director of the schizophrenia research program at the National Institute of Mental Health (which has funded some of Malaspina’s work). “We’re talking about samples from Scandinavia, cohorts in the United States, Japan. This is not just a finding that pertains to Israeli citizens or people of Jewish background.”

Excited about the potential of further studies in the Israeli population, Malaspina investigated whether father’s age might have an effect on children’s intelligence. Studies have shown that teenagers who later develop schizophrenia have slightly lower IQs than those who remain healthy. This time, Malaspina and Reichenberg combined information on the Israeli children with the medical and intelligence tests done on their parents. The children of older fathers showed a drop in nonverbal intelligence, measured by such tasks as remembering a series of numbers or solving visual problems. The supposition is that whatever is increasing the risk of schizophrenia might also be affecting brain pathways associated with intelligence.

The researchers knew that the draft-induction tests identified young men and women with autism, and they realized they could look at that, too, to see whether it was linked to fathers’ age. “There are similarities between autism and schizophrenia—they both have very severe social deficits,” said Reichenberg. “There was some reason to think similar risk factors might be involved.” In 2006, he, Malaspina, and their colleagues published the report showing that the children of men forty or older were six times as likely as the kids of men under thirty to develop autism or a related disorder. That’s the study I heard about the day after our son was born.

Autism spectrum disorders occurred at a rate of 6 in 10,000 in the children of the younger fathers, and 32 in 10,000 among the children of the older fathers. (That’s closer to five times the risk, but statistical adjustments showed the risk was actually about six times higher in the offspring of the older dads.) In the children of fathers over fifty, the risk was 52 in 10,000.

Reichenberg interprets that as a very solid finding. The study couldn’t absolutely rule out some effect of older mothers, but he was confident that it was the fathers who were responsible for the increased autism risk. He and Malaspina considered the same question that had been raised in connection with the schizophrenia studies: Would fathers who are a little socially isolated or aloof, with minor language deficits—whom we might think of as a little bit autistic—take longer to get married? If so, it would mean the autism risk was due to something different about the fathers—not their age.

There were a couple of arguments against that idea. First, the risk of autism rose smoothly with increasing age, through the thirties, forties, and fifties. If the risk of autism were somehow related to social or language problems in the fathers, it shouldn’t track age so closely. Secondly, the same argument has been made about mothers, some of whom, like men, might be said to be a little bit autistic. But the researchers didn’t find a clear link between mothers’ age and the risk of autism. Reichenberg and Malaspina are convinced the link to older fathers is real. And so are many other researchers.

Their findings have since been repeated and extended in a variety of ways. For example, researchers have looked at the genetics of older fathers to try to figure out what it might be in their genes that adversely affects their children. Schizophrenia and autism have been linked to a genetic mutation called a copy number variant, in which a section of DNA is mistakenly copied one or more extra times and inserted into the sequence, or a section is deleted. When male mice of various ages were bred with young female mice, data showed that the offspring of the older males were much more likely to have new mutations of this kind than were the offspring of younger males. These mutations might therefore be the link between older fathers and the increased risk of schizophrenia and autism in their children. More mutations lead to a higher incidence of illness.

But does the same thing happen in humans? Researchers collected genetic information on 3,443 patients with intellectual disabilities—delayed intellectual development, or problems with social skills or taking care of themselves. They found that most of the subjects with copy number variants had inherited them from their fathers, and the mutations were especially associated with older fathers.

Reichenberg, continuing his research on older fathers, bred female mice with older males, and again with younger males. Offspring of the older fathers engaged in less social interaction with other mice and were more reluctant to explore a new environment. These are among the kinds of behavior problems sometimes seen in psychiatric illnesses.

Malaspina asked Jay Gingrich, a psychiatrist and neuroscientist at Columbia who works with mice, to join her in looking at the offspring of older males. Gingrich can’t ask his mice whether they’re suffering delusions or hearing voices. But he can give them tests that are analogous to those that people with schizophrenia have difficulty passing. One such test is to gently drop a young mouse into the center of a box about the size of a cafeteria tray—a place he’s never seen before—and measure how much he wanders. If he shivers and stays where he is, he’s showing that he has a deficit in a part of the brain known to be affected in schizophrenia. When Gingrich ran the tests, the pups of older fathers were slower to explore these unfamiliar environments than the offspring of younger fathers.

Gingrich found the same kind of paternal-age-related decline using an entirely different test. This time he looked at how mice reacted when they were startled by a loud sound. Mice are like people—when they hear a loud noise, they jump. And there’s more similarity than that: when either mice or people hear a soft sound before being startled by a loud noise, they don’t jump as much at the noise. It’s called pre-pulse inhibition: the soft pulse inhibits the reaction to the louder one. “It’s abnormal in a number of neuropsychiatric disorders, including schizophrenia, autism, obsessive-compulsive disorders, and some of the others,” Gingrich told me. And, he found, it was more likely to be abnormal in mice with older fathers. Indeed, Gingrich thought the finding was almost too good to be true, and he didn’t believe it at first. It wasn’t until he and a postdoctoral student, Maria Milekic, had collected data on about one hundred offspring of younger dads and another hundred pups of older dads that he was convinced that the results were correct.

“We think this is a major cause of sporadic schizophrenia,” Malaspina said. That would make it a major cause of schizophrenia, period, because 80 percent of cases are sporadic (that is, not occurring in families with schizophrenia).

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There has been much talk of an increase in autism in recent years. Some say it’s a real increase; others say it’s because doctors are looking more carefully for it and therefore finding more cases. I asked Reichenberg whether the increase in the number of older fathers could explain a rise in autism cases. “I think there is a true increase in autism, and advancing paternal age might help explain some of that increase. But there is no proof. There might be a lot of other risk factors that have been increasing over the years,” he said.

The idea that the rise in autism is due to the growing number of older fathers got a tremendous boost in the summer of 2012, when the Icelandic geneticist Kári Stefánsson and his colleagues looked at the question. Stefánsson is the chief executive of deCODE Genetics, a company based in Reykjavík, which bases its research partly on genetic samples from 140,000 people in Iceland and a family tree of the entire Icelandic population going back a thousand years. They compared the gene sequences of seventy-eight couples and their children and found that fathers were far more likely to pass on new mutations to the children than were mothers. And the number of mutations fathers passed along rose exponentially with their age. A thirty-six-year-old man will pass on twice as many mutations as a twenty-year-old father, and a seventy-year-old father will pass on eight times as many. They also estimated that an Icelandic child born in 2011 would have more new mutations than a child born in 1960. During that time, the average age of Icelandic fathers rose from twenty-eight to thirty-three. Most of these mutations are harmless, but some were indeed linked to the rise in schizophrenia and autism in Iceland.

The results suggest a new answer to the nagging question of why autism seems to be on the rise. Stefánsson calculated how many new cases of autism could arise as the consequence of fathers becoming older, on average. The mutations that he found in the children of older fathers could be the cause of 20 to 30 percent of all cases of autism, a stunningly high percentage. Stefánsson’s study brought the concerns about older fathers to the front pages and home pages of newspapers and websites around the world.