Older fathers linked to autism, schizophrenia

LOS ANGELES — Men who become fathers later in life pass on more brand-new genetic mutations to their offspring, a study has found — probably contributing to disorders such as autism and schizophrenia in the next generation.

The finding, published online Wednesday in the journal Nature, buttresses earlier observations that rates of autism and some other disorders are more prevalent in children born of older fathers, sometimes by a factor of two or more, experts said. Although this has been observed for years from population studies, scientists had not known what lay behind it.

The new research, made possible by recent advances in DNA-sequencing technology, also should help correct an overemphasis on the riskiness of women giving birth at older ages, some researchers said.

Although older mothers are at higher risk for complications such as diabetes during pregnancy and are more likely to have children with chromosomal disorders such as Down syndrome, the study found that practically all of the new mutations detected in children came from the father.

And the older the father, the more mutations he passed on.

A man aged 29.7 at the time he fathered a child contributed 63 new mutations on average to his offspring, the authors found, and a man age 46.2 contributed 126 mutations — a doubling, the authors calculated.

Many of the mutations would confer no effect either for good or ill on the children, scientists noted. But some would — and that is significant because in developed countries there has been a shift over the decades toward older men fathering children, said study senior author Dr. Kari Stefansson.

Stefansson, who is a human geneticist and neurologist at the University of Iceland and the company deCODE Genetics in Reykjavík, noted for example that the average age of Iceland’s fathers at the time of a child’s conception was 34.9 in 1900, falling to 27.9 in 1980, then rising back up again to 33 in 2011.

“Similar changes have taken place all over the Western world,” Stefansson said. “It’s very likely to have made meaningful contributions to increased diagnoses of autism in our society. What percentage is due to that and what percentage is due to increased focus on diagnosis, I cannot tell you.”

Stefansson and coauthors sequenced the entire genomes of 78 so-called “trios” — father, mother and child — many times over to detect tiny mutations in which a single “letter” in the DNA code had been altered. Of the children, 44 had received a diagnosis of autism spectrum disorder and 21 had schizophrenia. The genetic codes of five grandchildren were sequenced, too.

The scientists were able to identify stretches of DNA that had come from the father or mother. But they also could detect new mutations in the child that did not exist in the genome of either parent.

To be sure that these were bona fide new mutations and not an error of DNA sequencing, the genome of each person was sequenced many times over and the genomes of 1,859 other Iceland residents were sequenced as well to exclude mutations that already existed in the general population.