By Deborah Levenson
RESEARCH UPDATE COMMON GENETIC VARIANTS LINKED WITH LARGE PERCENTAGE OF AUTISM RISK Study finds spontaneous mutations are less-significant risk factors early half of the inherited risk for autism spectrum disorder comes from common genetic variants, not spontaneous mutations, according to a recent study. Reporting in a recent issue of Nature Genetics, researchers found that although 14% of patients with autism carried de novo mutations—which can contribute substantially to individual risk—those mutations accounted for just 2.6% of variance in disease risk while common mutations accounted for 49% [Gaugler et al., 2014]. For their study, investigators did array-based, common-variant genotyping on more than 3,000 Swedish patients enrolled in the Population-Based Autism Genetics and Environment Study (PAGES). Researchers estimated autism’s narrow-sense heritability at 52.4%, with most due to common variations. Genetic variation accounted for roughly 60% of the liability of autism. Researchers did not identify specific genetic risk factors. Instead, they devised a genetic model to search for more clues to the molecular underpinnings of autism. “What we’ve learned here is that there is a basic background risk a couple carries,” says the study’s co–senior author Kathryn Roeder, PhD, Professor of Statistics and Computational Biology at Carnegie Mellon University in Pittsburgh. “If their child has a de novo mutation on top of that, it could push that individual over the edge.”
The Study Using new statistical methods, Gaugler et al sorted out heritability of autism. These methods included machine learning, © 2014 Wiley Periodicals, Inc.
© Constantin-Ciprian / Shutterstock.com
N
Genetic mutations in DNA (illustrated above) have been linked with increased risk of autism.
which involves software that learns from data, and dimension reduction, which diminishes the number of random variables under consideration. After analyzing data from PAGES, the researchers compared their results with a parallel study of 1.6 million families affected by autism, also conducted in Sweden. The second study had considered age of fathers when their children were born and parents’ psychiatric history, as well as data from cousins and twins. Data from the second study allowed Dr. Roeder’s team to discern how variables such as added genetic and environmental effects contribute to autism risk. “A special feature of our research was that we were able to look at distant relatives who were third or fourth cousins. They didn’t know each other and had no environment in common, so it was a clean
study design,” says Dr. Roeder. “We looked for unusual correlations. If two people with autism were a little [genetically] more alike than we’d expect, there were probably causal genes involved.” “We expected to find common variants for autism because they exist for every trait,” she adds. “The new [statistical and molecular] tools allowed us to divide them into common and rare variants.”
Role of Genetic Variants Explored While few studies have looked at the role of common variants in autism, an earlier study that involved Dr. Roeder also examined the role of additive genetic effects in autism. That paper, published in 2012, showed that myriad common variants, each with very small effect, impact risk for autism [Klei et al., 2012]. Dr. Roeder and other autism vii
RESEARCH UPDATE CONTINUED researchers note that the findings regarding the contributions of common and rare variants must be confirmed in larger studies. However, her paper “supports what people have hypothesized for a while,” says G. Bradley Schaefer, MD, Professor of Pediatrics at the University of Arkansas for Medical Sciences, Section Chief of Genetics and Metabolism at Arkansas Children’s Hospital in Little Rock, and senior author of the American College of Medical Genetics and Genomics (ACMG) guidelines on autism testing. “The idea is that the right combination of little genetic changes can cause autism,” Dr. Schaefer points out. “This paper is one of the first to look at the mechanistics involved.” Noting that genetic testing currently yields diagnoses in 35% to 40% of cases, Dr. Schaefer predicts the findings may eventually lead to more answers. But for
now, the paper does send an immediate message to geneticists, he adds. “Just because testing doesn’t find an answer does not mean the cause is not genetic. Diagnosis is still potentially achievable in a little time,” he says. Increasing use of genomic testing and longitudinal studies that confirm Dr. Roeder’s findings may lead to changes in what ACMG guidelines consider first-, second-, and third-tier tests for diagnosing autism, Dr. Schaefer adds. The findings may represent a shift in thinking about autism. Both Dr. Roeder and Maximilian Muenke, MD, Chief and Senior Investigator in the Medical Genetics Branch of the National Human Genome Research Institute, note that research in recent years has focused on the role of de novo mutations in autism. “The important idea that most autism is due to common variations is a paradigm shift,” Dr. Muenke says. The
finding that heritability exceeds 50% is also crucial, he notes. “The main cause is not environmental. It’s not TV, not sugar, vaccines, or video games. It is indeed genetics.”
References Gaugler T, Klei L, Sanders S, Corneliu B, Goldberg A, Lee S, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman C, Devlin B, Roeder K, Buxbaum J. 2014. Most genetic risk for autism resides with common variation. Nat Genet 46;881–885. Klei L, Sanders S, Michael M, Hus V, Lowe J, Willsey AJ, Moreno-De-Luca D, Yu T, Fombonne E, Geschwind D, Grice D, Ledbetter D, Lord C, Shrikant Mane S, Martin C, Martin D, Morrow E, Walsh D, Melhem N, Chaste P, Sutcliffe S, State M, Cook E, Roeder K, Devlin B. 2012. Common genetic variants, acting additively, are a major source of risk for autism. Nature 511(7510):421–427. DOI 10.1002/ajmg.a.36817 2014 Wiley Periodicals, Inc.
TESTING UPDATE SOMATIC MOSAICISM IN PARENTS MAY CAUSE SINGLE-GENE DISORDERS IN CHILDREN Latest study calculates incidence of parental mosaicism higher than previous research suggests
A
small but significant proportion of children with single-gene disorders apparently caused by spontaneous mutations actually inherit diseases from unaffected parents who harbor genetic variations in their blood cells, according to recent research. The phenomenon of mutationcontaining somatic cells coexisting with normal cells in blood or tissue, known as mosaicism, may affect up to 4% of parents of children with single-gene disorders, according to research in the August 7 issue of The American Journal of Human Genetics [Campbell et al., 2014]. Discovered decades ago, mosaicism in parents arises during formation of their own egg and sperm cells, or early in the parent’s own embryonic development viii
when somatic cells divide. If only a small proportion of cells are affected, these mosaic parents may have no noticeable disease, but pathogenic mutations may be passed on from the germline and cause disorders in the next generation. While mosaicism is well-known and documented in some disorders, its overall incidence had not been measured until now. The study shows “mosaicism happens more frequently than we thought,” says first author Ian Campbell, an MD/PhD student in the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston. The paper is important because “it puts data to what we’ve always suspected,” adds Nancy Spinner, PhD, Professor of Pathology and Laboratory Medicine
at the University of Pennsylvania in Philadelphia and an expert on mosaicism.
The Study The impetus for the study—led by Pawel Stankiewicz, MD, PhD, and James R. Lupski MD, PhD—came from a United Kingdom–based colleague’s request for help in understanding the recurrence of Smith-Magenis syndrome in three children born to one mother and two different fathers. The Baylor researchers tested the mother’s blood with a form of polymerase chain reaction (PCR) that made many copies of the region of DNA where the children’s deletions occurred and found the mutation in some of her blood cells. When the researchers tested another
RESEARCH UPDATE COMMON GENETIC VARIANTS LINKED WITH LARGE PERCENTAGE OF AUTISM RISK Study finds spontaneous mutations are less-significant risk factors early half of the inherited risk for autism spectrum disorder comes from common genetic variants, not spontaneous mutations, according to a recent study. Reporting in a recent issue of Nature Genetics, researchers found that although 14% of patients with autism carried de novo mutations—which can contribute substantially to individual risk—those mutations accounted for just 2.6% of variance in disease risk while common mutations accounted for 49% [Gaugler et al., 2014]. For their study, investigators did array-based, common-variant genotyping on more than 3,000 Swedish patients enrolled in the Population-Based Autism Genetics and Environment Study (PAGES). Researchers estimated autism’s narrow-sense heritability at 52.4%, with most due to common variations. Genetic variation accounted for roughly 60% of the liability of autism. Researchers did not identify specific genetic risk factors. Instead, they devised a genetic model to search for more clues to the molecular underpinnings of autism. “What we’ve learned here is that there is a basic background risk a couple carries,” says the study’s co–senior author Kathryn Roeder, PhD, Professor of Statistics and Computational Biology at Carnegie Mellon University in Pittsburgh. “If their child has a de novo mutation on top of that, it could push that individual over the edge.”
The Study Using new statistical methods, Gaugler et al sorted out heritability of autism. These methods included machine learning, © 2014 Wiley Periodicals, Inc.
© Constantin-Ciprian / Shutterstock.com
N
Genetic mutations in DNA (illustrated above) have been linked with increased risk of autism.
which involves software that learns from data, and dimension reduction, which diminishes the number of random variables under consideration. After analyzing data from PAGES, the researchers compared their results with a parallel study of 1.6 million families affected by autism, also conducted in Sweden. The second study had considered age of fathers when their children were born and parents’ psychiatric history, as well as data from cousins and twins. Data from the second study allowed Dr. Roeder’s team to discern how variables such as added genetic and environmental effects contribute to autism risk. “A special feature of our research was that we were able to look at distant relatives who were third or fourth cousins. They didn’t know each other and had no environment in common, so it was a clean
study design,” says Dr. Roeder. “We looked for unusual correlations. If two people with autism were a little [genetically] more alike than we’d expect, there were probably causal genes involved.” “We expected to find common variants for autism because they exist for every trait,” she adds. “The new [statistical and molecular] tools allowed us to divide them into common and rare variants.”
Role of Genetic Variants Explored While few studies have looked at the role of common variants in autism, an earlier study that involved Dr. Roeder also examined the role of additive genetic effects in autism. That paper, published in 2012, showed that myriad common variants, each with very small effect, impact risk for autism [Klei et al., 2012]. Dr. Roeder and other autism vii
RESEARCH UPDATE CONTINUED researchers note that the findings regarding the contributions of common and rare variants must be confirmed in larger studies. However, her paper “supports what people have hypothesized for a while,” says G. Bradley Schaefer, MD, Professor of Pediatrics at the University of Arkansas for Medical Sciences, Section Chief of Genetics and Metabolism at Arkansas Children’s Hospital in Little Rock, and senior author of the American College of Medical Genetics and Genomics (ACMG) guidelines on autism testing. “The idea is that the right combination of little genetic changes can cause autism,” Dr. Schaefer points out. “This paper is one of the first to look at the mechanistics involved.” Noting that genetic testing currently yields diagnoses in 35% to 40% of cases, Dr. Schaefer predicts the findings may eventually lead to more answers. But for
now, the paper does send an immediate message to geneticists, he adds. “Just because testing doesn’t find an answer does not mean the cause is not genetic. Diagnosis is still potentially achievable in a little time,” he says. Increasing use of genomic testing and longitudinal studies that confirm Dr. Roeder’s findings may lead to changes in what ACMG guidelines consider first-, second-, and third-tier tests for diagnosing autism, Dr. Schaefer adds. The findings may represent a shift in thinking about autism. Both Dr. Roeder and Maximilian Muenke, MD, Chief and Senior Investigator in the Medical Genetics Branch of the National Human Genome Research Institute, note that research in recent years has focused on the role of de novo mutations in autism. “The important idea that most autism is due to common variations is a paradigm shift,” Dr. Muenke says. The
finding that heritability exceeds 50% is also crucial, he notes. “The main cause is not environmental. It’s not TV, not sugar, vaccines, or video games. It is indeed genetics.”
References Gaugler T, Klei L, Sanders S, Corneliu B, Goldberg A, Lee S, Mahajan M, Manaa D, Pawitan Y, Reichert J, Ripke S, Sandin S, Sklar P, Svantesson O, Reichenberg A, Hultman C, Devlin B, Roeder K, Buxbaum J. 2014. Most genetic risk for autism resides with common variation. Nat Genet 46;881–885. Klei L, Sanders S, Michael M, Hus V, Lowe J, Willsey AJ, Moreno-De-Luca D, Yu T, Fombonne E, Geschwind D, Grice D, Ledbetter D, Lord C, Shrikant Mane S, Martin C, Martin D, Morrow E, Walsh D, Melhem N, Chaste P, Sutcliffe S, State M, Cook E, Roeder K, Devlin B. 2012. Common genetic variants, acting additively, are a major source of risk for autism. Nature 511(7510):421–427. DOI 10.1002/ajmg.a.36817 2014 Wiley Periodicals, Inc.
TESTING UPDATE SOMATIC MOSAICISM IN PARENTS MAY CAUSE SINGLE-GENE DISORDERS IN CHILDREN Latest study calculates incidence of parental mosaicism higher than previous research suggests
A
small but significant proportion of children with single-gene disorders apparently caused by spontaneous mutations actually inherit diseases from unaffected parents who harbor genetic variations in their blood cells, according to recent research. The phenomenon of mutationcontaining somatic cells coexisting with normal cells in blood or tissue, known as mosaicism, may affect up to 4% of parents of children with single-gene disorders, according to research in the August 7 issue of The American Journal of Human Genetics [Campbell et al., 2014]. Discovered decades ago, mosaicism in parents arises during formation of their own egg and sperm cells, or early in the parent’s own embryonic development viii
when somatic cells divide. If only a small proportion of cells are affected, these mosaic parents may have no noticeable disease, but pathogenic mutations may be passed on from the germline and cause disorders in the next generation. While mosaicism is well-known and documented in some disorders, its overall incidence had not been measured until now. The study shows “mosaicism happens more frequently than we thought,” says first author Ian Campbell, an MD/PhD student in the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston. The paper is important because “it puts data to what we’ve always suspected,” adds Nancy Spinner, PhD, Professor of Pathology and Laboratory Medicine
at the University of Pennsylvania in Philadelphia and an expert on mosaicism.
The Study The impetus for the study—led by Pawel Stankiewicz, MD, PhD, and James R. Lupski MD, PhD—came from a United Kingdom–based colleague’s request for help in understanding the recurrence of Smith-Magenis syndrome in three children born to one mother and two different fathers. The Baylor researchers tested the mother’s blood with a form of polymerase chain reaction (PCR) that made many copies of the region of DNA where the children’s deletions occurred and found the mutation in some of her blood cells. When the researchers tested another
