Summary: Researchers have identified brain differences in people with a genetic risk factor for autism and schizophrenia.
Deletions or duplications of DNA along 22nd chromosome hint at biological underpinnings of these disorders.
A UCLA study characterizes, for the first time, brain differences between people with a specific genetic risk for schizophrenia and those at risk for autism, and the findings could help explain the biological underpinnings of these neuropsychiatric disorders.The research, published May 23 in the Journal of Neuroscience, sheds light on how an excess, or absence, of genetic material on a particular chromosome affects neural development.
“Notably, the opposing anatomical patterns we observed were most prominent in brain regions important for social functioning,” said Carrie Bearden, lead author of the study and a professor of professor of psychiatry and biobehavioral sciences, and of psychology, at UCLA. “These findings provide clues into differences in brain development that may predispose to schizophrenia or autism.”
Bearden’s earlier research had focused on children with abnormalities caused by missing sections of genetic material on chromosome 22, in a location known as 22q11.2. The disorder, called 22q11.2-deletion syndrome, can cause developmental delays, heart defects and distinct facial features. It also confers the highest-known genetic risk for schizophrenia.
Then she learned that people with 22q duplication — abnormal repetition, or duplication, of genetic material in chromosome 22 — had learning delays and sometimes autism, but a lower risk for schizophrenia than that found in the general population. In other words, duplication of genetic material in this region seemed to provide some protection against schizophrenia.
For the current study, Bearden, who is part of the UCLA Semel Institute for Neuroscience and Human Behavior, conducted MRI scans of 143 study participants: 66 with 22q deletions, 21 with 22q duplications, and 56 without the genetic mutation.
Those in the group with 22q deletion, which carries the risk for schizophrenia, had thicker gray matter, but less brain surface area — a measure which relates to how folded the brain is — compared to those in the duplication group. The people in the 22q duplication group, who at risk for autism, had the opposite pattern, with thinner gray matter and larger brain surface area.
“The next question is how does brain anatomy — and brain function — relate to psychiatric outcomes? These findings provide a snapshot,” Bearden said. “We are now conducting follow-up studies to track predictors of outcome over time. Those are the puzzle pieces that are next on our list to disentangle.”
These structures are not sole determinants of schizophrenia or autism, Bearden said, but rather, more dots in the connect-the-dots puzzle of understanding these disorders. Observing this group of people over time could provide insights on how other risk factors or life events, such as puberty, affect the mind.
Bearden says she and her team are collaborating with other scientists to investigate brain structural differences in animal models, to find out what causes them at the cellular level.
The study’s first author is Amy Lin, a doctoral student in the UCLA neuroscience program. Other authors are Ariana Vajdi, Daqiang Sun, Rachel Jonas, Leila Kushan-Wells, Laura Pacheco Hansen, Emma Krikorian, Deepika Dokuru, Gerhard Helleman, all of UCLA; Maria Jalbrzikowski of the University of Pittsburgh Medical Center; Paul Thompson and Boris Gutman of USC; and Christopher Ching of UCLA and USC.
Funding: The research was funded by the Simons Foundation, the National Institute of Mental Health (RO1 MH085953), and a Neurobehavioral Genetics Predoctoral Training Grant (5T32MH073526).
Source: Leigh Hopper – UCLA
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry” by Amy Lin, Christopher R. K. Ching, Ariana Vajdi, Daqiang Sun, Rachel K. Jonas, Maria Jalbrzikowski, Leila Kushan-Wells, Laura Pacheco Hansen, Emma Krikorian, Boris Gutman, Deepika Dokoru, Gerhard Helleman, Paul M. Thompson and Carrie E. Bearden in Journal of Neuroscience. Published online May 23 2017 doi:10.1523/JNEUROSCI.3759-16.2017
Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry
Reciprocal chromosomal rearrangements at the 22q11.2 locus are associated with elevated risk of neurodevelopmental disorders. The 22q11.2 deletion confers the highest known genetic risk for schizophrenia, but a duplication in the same region is strongly associated with autism and is less common in schizophrenia cases than in the general population. Here we conducted the first study of 22q11.2 gene dosage effects on brain structure in a sample of 143 human subjects: 66 with 22q11.2 deletions (22q-del; 32 males), 21 with 22q11.2 duplications (22q-dup; 14 males), and 56 age- and sex-matched controls (31 males). 22q11.2 gene dosage varied positively with intracranial volume, gray and white matter volume, and cortical surface area (deletion < control< duplication). In contrast, gene dosage varied negatively with mean cortical thickness (deletion > control > duplication). Widespread differences were observed for cortical surface area with more localized effects on cortical thickness. These diametric patterns extended into subcortical regions: 22q-dup carriers had a significantly larger right hippocampus, on average, but lower right caudate and corpus callosum volume, relative to 22q-del carriers. Novel subcortical shape analysis revealed greater radial distance (thickness) of the right amygdala and left thalamus, and localized increases and decreases in sub-regions of the caudate, putamen, and hippocampus in 22q-dup relative to 22q-del carriers. This study provides the first evidence that 22q11.2 is a genomic region associated with gene-dose-dependent brain phenotypes. Pervasive effects on cortical surface area imply that this copy number variant affects brain structure early in the course of development.
Probing naturally occurring reciprocal copy number variation in the genome may help us understand mechanisms underlying deviations from typical brain and cognitive development. The 22q11.2 genomic region is particularly susceptible to chromosomal rearrangements and contains many genes crucial for neuronal development and migration. Not surprisingly, reciprocal genomic imbalances at this locus confer some of the highest known genetic risks for developmental neuropsychiatric disorders. Here we provide the first evidence that brain morphology differs meaningfully as a function of reciprocal genomic variation at the 22q11.2 locus. Cortical thickness and surface area were affected in opposite directions with more widespread effects of gene dosage on cortical surface area.
“Mapping 22q11.2 Gene Dosage Effects on Brain Morphometry” by Amy Lin, Christopher R. K. Ching, Ariana Vajdi, Daqiang Sun, Rachel K. Jonas, Maria Jalbrzikowski, Leila Kushan-Wells, Laura Pacheco Hansen, Emma Krikorian, Boris Gutman, Deepika Dokoru, Gerhard Helleman, Paul M. Thompson and Carrie E. Bearden in Journal of Neuroscience. Published online May 23 2017 doi:10.1523/JNEUROSCI.3759-16.2017