Extremely-rare variants level to new autism candidate genes | Spectrum
An analysis of entire genome sequences from thousands of families – one of the largest studies of its kind to date – has linked 163 new genes to autism. The study appeared in Nature Genetics today.
The newly linked genes harbor extremely rare inherited genetic variants – changes in the genome that were passed on from non-autistic parents to their autistic offspring. The variants are so rare that each can only be found in a single family.
Most previous genome sequencing studies for autism have focused on spontaneous or de novo mutations – genetic changes that occur in a child but not in either parent. These mutations are relatively easy to spot and have linked hundreds of genes to autism.
“What is unique about this work is that it deals with a type of genetic variant that has not been studied as much in autism,” says Sagiv Shifman, a professor of genetics at the Hebrew University of Jerusalem, Israel who was not involved in the study. “De novo mutations are just easier to study. They are low-hanging fruit. “
The new work is based on sequences of 4,364 autistic people and their non-autistic siblings and parents from five data sets, some of which have not yet been published.
Although the data sets cover entire genomes, the researchers initially focused their analysis on ultra-rare variants that were predicted to disrupt protein-coding genes.
“We thought we had a slightly better chance of recognizing a signal in protein-coding genes than other types of variations that are not as well understood,” says study researcher Amy Wilfert, Senior Research Fellow in Evan Eichler’s laboratory at the university of Washington in Seattle.
The researchers found that autistic children 1.2 to 1.3 times more likely than their non-autistic siblings to inherit an extremely rare variant of genes previously associated with autism. They replicated the finding in an additional set of whole exome sequences from 6,453 autistic children and their families.
These changes account for about 4.5 percent of the risk of autism, the researchers estimate – a number comparable to that for de novo mutations, suggesting that rare inherited variations are a little explored but important contributor to autism.
“With regard to population risk, these genetic variants can contribute almost as much as more well-known risk factors such as de novo mutations,” says Wilfert.
The results are also in line with previous studies examining inherited variations, but in data that were limited to the exome or protein-coding regions of the genome from a smaller number of families.
“This study gives me great confidence that all of the genome sequencing sets we are generating are high quality and worth analyzing. You get the same results from sequencing the entire genome that others get from the exome alone, ”said David Cutler, an adjunct professor of human genetics at the Emory University School of Medicine in Atlanta, Georgia. “We’re probably going the right way to understand autism.”
A second analysis focused on genes with extremely rare variants that do not tolerate mutations and that have not been associated with autism in studies of de novo mutations. It identified 163 genes that, if changed, can increase a person’s chances of developing autism. None of these genes appear in SFARI Genes, a database that catalogs more than 1,000 genes associated with the disease. (The database is funded by the Simon’s Foundation, Spectrum’s parent organization.)
Almost half of the genes identified in the new study are involved in key cellular processes such as protein regulation. Many are also expressed in certain cell types in the human cortex or the outer layer of the brain during development.
“It was really exciting to see that the gene candidates we identified differ from the genes that have been identified in de novo mutation studies so far,” says Wilfert. “They end up converging on the same networks, suggesting common pathways, but different genes play a role.”
Although the researchers only looked at protein-coding genes, their data sets contain the entire genome – including any letters between the genes – for thousands of families. These data will be a useful starting point for other teams hoping to understand how regulatory or non-coding parts of the genome also contribute to autism, say Cutler and Shifman.
The full data is uploaded to the genotype and phenotype database, Wilfert says, so other researchers can explore and ask new questions.