Researchers have identified yet another common genetic variation that appears to be associated with autism.  The results, published this week in the journal Molecular Psychiatry, show that each copy of an G at rs12603112 in the CACNA1G gene increase the odds of autism in boys (but not girls) by about 2.2 times.

(23andMe customers can check their data for rs12603112 using the Browse Raw Data feature.)

But Stanley Nelson, senior author of the study and a 23andMe scientific advisor, points out that the G version of this SNP is actually fairly common.

“Most people with the risk genotype will not develop autism.”

For more on this story:

• Gene May Offer Clue Why Autism Risk Is Fourfold Higher in Boys
• A Genetic Clue to Why Autism Affects Boys More
• UCLA scientists identify new gene linked to autism risk

ShareThis

New genetic evidence adds strength to the theory that abnormal connections between brain cells are at the root of autism.

Autism is just one of the autism spectrum disorders (ASDs), a group of childhood developmental disorders that cause impairments in verbal communication, social interaction and behavior.  An estimated one in 150 children in the United States is affected.  Studies have indicated a strong genetic contribution to ASDs, but only a few rare genetic risk factors have been identified so far.  Now two reports, published online today by the journal Nature, demonstrate an association between the risk for autism and common genetic variants in and around genes that affect how brain cells migrate to the correct places in the brain and adhere to one another.

“Although we cannot immediately apply this research to clinical treatment, these findings increase our understanding of how autism spectrum disorders arise, and may in time foster the development of strategies for prevention and early treatment,” said Susan Levy, a co-author of both studies.

A large research team, led by Hakon Hakonarson of Children’s Hospital of Philadelphia and including scientists from more than a dozen research institutions, analyzed DNA from more than 10,000 people with European ancestry, including people with autism, their families and volunteers from the community.  They found several SNPs associated with autism.  All were located in a region of DNA between two genes, CDH9 and CDH10, which encode proteins called cadherins.

“These molecules are expressed on the cell surfaces of neurons, and they are involved with shaping both the physical structure of the developing brain and the functional connections among different brain regions.  Although a particular gene variant may contribute a small risk for an ASD in a particular individual, we estimate that the variants we discovered may contribute to as many as 15 percent of ASD cases in a population,” said Hakonarson in a statement.

The strongest signal came from rs4307059 — compared to two copies of a C, each copy of the more common T version increased the odds of autism by 1.19 times.

(23andMe customers can check their data using the Browse Raw Data feature.)

Analysis of human fetal brain tissue revealed that the CDH10 gene is expressed at high levels in the frontal cortex, a brain region critical for language, social behavior and complex thought processes.

“It’s no coincidence that a gene linked to autism has a higher concentration in key brain regions that regulate speech and the ability to interpret social interaction. Our research suggests that CDH10 is switched on at a very early stage and plays an important role in regulating the developing brain.  This prenatal activity somehow makes the infant more susceptible to autism,” said Daniel Geschwind, a study co-author and director the UCLA Center for Autism Treatment and Research, in a statement.

In the second Nature study, also led by Hakonarson, researchers turned their focus away from SNPs — single letter differences in the genetic code — and instead investigated the role of copy number variations (CNVs) — small deletions and duplications DNA — in autism.

The CNVs Hakonarson and co-workers identified occurred mostly in genes that fall into two biological pathways: cell adhesion, the same pathway affected by the SNPs found in the first study, and the ubiquitin degradation pathway, a kind of cellular waste disposal system.  Among other things, enzymes in the ubiquitin pathway are involved in eliminating connections between nerve cells by destroying cell adhesion proteins, suggesting that variants in this pathway might also be affecting cell-to-cell connections in the brain.

In addition to their genetic findings, the authors say that recent neuroimaging studies that have suggested underconnectivity in the brains of subjects with ASDs and neuroanatomy studies that have implicated abnormal brain development in the frontal lobes of people with autism support the idea that altered cell-to-cell connections are a key component of autism.

Hakonarson and colleagues plan to continue researching autism, focusing their efforts on elucidating how the genetic variations they have identified might cause autism.  One experiment suggested by Hakonarson is to mutate cell adhesion proteins like cadherins in mice and look for changes in social behavior that mimic those seen in humans with autism.

Note:
A much smaller study, appearing online today in Molecular Psychiatry, found another genetic variant associated with autism.  Each copy of the A version of rs2217262 in the DOCK4 gene increased the odds of autism by 2.28 times.  Note that almost 90% of people with European ancestry have two copies of the A version of this SNP, meaning that these results really mean that the rare C version of the SNP is protective against autism. The authors of the study say that DOCK4 is involved in the extensions of brain cells that form synapses, the connections between brain cells.

ShareThis

Autism, a neurological disorder that impairs a person’s ability to communicate with and relate to others, affects one in every 150 American children. Genetics is thought to be at least partly to blame for this condition, but research aimed at finding the genes involved has been frustratingly slow.

This is due at least in part to the fact that it’s unlikely that there is one or even a small number of “autism genes.” Autism is a “spectrum disorder” that affects individuals differently and to varying degrees.  There are probably different genetic and environmental factors at work in different types of autism.

New research, published online this week by the journal Pediatrics, may shed light on the genetic underpinnings of at least one subtype of autism. Research has shown that gastrointestinal (GI) problems are more common in people with autism than the general population.  The new work shows that variation in a signaling protein involved in both brain development and gastrointestinal repair may contribute to an increased risk for the types of autism that include gastrointestinal dysfunction.

“Our study is the first to bring together genetic risk for autism and co-occurring GI disorders in a way that provides a biologically plausible explanation for why they are seen together so often,” said Pat Levitt, director of the Zilkha Neurogenetic Institute at the Keck School of Medicine of USC and senior author of the study, in a statement.

Previous research by Levitt’s group showed that a SNP in the Met gene increases the risk of autism. People with one copy of the variation have 1.67 times the risk of autism and people with two copies have 2.27 times the risk.

The current study looked at 918 people from 214 families with at least one child affected by autism and found that the association between the condition and the SNP holds only in those patients with GI disorders such as chronic constipation or diarrhea, irritable bowel syndrome, gastroesophogeal reflux or peptic ulcer disease.

The researchers suggest that types of autism that include GI disorders may be a distinct class of the condition, with the Met gene playing an important part.   Their previous work demonstrated that the version of the variation that increases the risk of autism reduces the amount of protein made from the Met gene.  People with autism were also shown to have less Met protein in their brains than age and gender matched controls.

The authors warn that their study was small and the association of the variation they focused on does not completely explain the high prevalence of GI disorders in people with autism.  They say their results should be considered “exploratory.” Nevertheless, the findings may bring researchers closer to understanding the complex genetics of autism.

ShareThis