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Summary of Advances

In Autism Research


Genetic and Environmental Factors

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.
Lawrence KE, Hernandez LM, Fuster E, Padgaonkar NT, Patterson G, Jung J, Okada NJ, Lowe JK, Hoekstra JN, Jack A, Aylward E, Gaab N, Van Horn JD, Bernier RA, McPartland JC, Webb SJ, Pelphrey KA, Green SA, Bookheimer SY, Geschwind DH, Dapretto M, GENDAAR Consortium. Brain. 2022;145:378-387 [PMID: 34050743]


Genes associated with autism impact activity in certain parts of the brain more in boys than in girls.

Background: Autism is diagnosed 3 to 4 times more often in boys than in girls, but the biological reasons for this difference are unclear. One potential explanation is that the gene differences associated with autism impact brain function more strongly in boys than girls. As a result, girls might need to accumulate a higher number of genetic differences to be develop autism-a hypothesis known as the female protective effect. This study explored specifically whether a subset of genes associated with autism may have effects on the brain's "functional connectivity," meaning how well brain regions communicate with one another. In particular, some genes associated with autism affect the connectivity of parts of the brain called the salience network, which plays a central role in determining what to pay attention to in an environment. This study compared functional connectivity in this network in both autistic and neurotypical boys and girls.

Methods & Findings: This study used a brain imaging technique called magnetic resonance imaging (MRI) to study functional connectivity in the brains of boys and girls (ages 8–17 years old) with and without autism. Researchers used DNA from either blood or saliva samples to determine the number of genetic differences associated with autism that each participant had. Brain imaging of autistic boys who had more gene differences associated with autism revealed increased communication between the salience network of the brain and regions involved in processing sensations, such as temperature, vibration, touch, and pain. Brain imaging in autistic girls did not show this relationship. The researchers also looked at boys and girls who had some gene differences associated with autism but did not have enough autistic traits to receive an autism diagnosis. The same distinction between sexes was observed: boys who had more genetic differences associated with autism but did not meet the criteria for ASD showed greater connectivity between the salience network and sensory regions of the brain in scans, but girls with some autism-associated genetic differences but without an ASD diagnosis did not exhibit this relationship.

Implications: These results suggest that some of the genes related to both autism and the functional connectivity of the salience network might have more influence on boys' brains than on girls' brains. Moreover, the increased connectivity between the attention and sensory regions of the brain may explain autistic boys' greater tendency to show repetitive movements compared to autistic girls. These repetitive behaviors are a key part of ASD diagnosis. Thus, these functional connectivity differences may be an illustration of the female protective effect and could play a role in the higher rate of ASD diagnosis in boys than in girls.

Developmental vitamin D and autism spectrum disorders: findings from the Stockholm Youth Cohort.
Lee BK, Eyles DW, Magnusson C, Newschaffer CJ, McGrath JJ, Kvaskoff D, Ko P, Dalman C, Karlsson H, Gardner RM. Mol Psychiatry. 2021;26:1578-1588. [PMID: 31695167]


Low vitamin D levels in pregnancy may be a contributing factor in the development of autism.

Background: Vitamin D, commonly referred to as the "sunshine vitamin," is a hormone that is important for brain development early in life. Vitamin D deficiency is common in pregnant women, and occurs more often in winter, northern countries, urban settings, and in dark-skinned individuals. A baby's brain may develop differently if concentrations of vitamin D are low prenatally (i.e., during pregnancy). This study investigated whether low levels of vitamin D during pregnancy and early in life can influence the likelihood of a later autism diagnosis.

Methods & Findings: This study used data from Sweden, which has several large, population-wide sources of data on maternal and child health. The researchers began by using a database containing health information for all children living in Stockholm County in Sweden. They examined health data from 3,006 children born between 1996 and 2000. To connect this health data to vitamin D levels, the researchers analyzed blood samples that are collected from all pregnant women and their newborns in Sweden. To avoid confusing the influence of familial factors (e.g., genetics) with maternal vitamin D levels, researchers also did an analysis comparing vitamin D levels in sibling pairs where one sibling has ASD and the other does not, reducing the chance that results could be affected by genetic and other shared family factors. The results of the study overall showed that children were 1.75 times more likely to be diagnosed with autism if their mothers had lower levels of vitamin D in the first trimester of pregnancy and if the children themselves had low vitamin D levels in their first month of life (the researchers considered vitamin D levels to be "low" if they were in the lower half of all the measured vitamin D levels in the study sample population). In addition, children with low vitamin D in the first month of life (i.e., neonates) were more likely to be diagnosed with autism regardless of their mothers' vitamin D levels during pregnancy.

Implications: Vitamin D is involved in a range of processes that are relevant to early brain development. This study found that higher concentrations of prenatal/neonatal vitamin D are associated with lower likelihood of ASD later in life. These results suggest a possible connection between autism and low levels of vitamin D during early brain development, especially during pregnancy and infanthood. However, it is not clear based on these data whether low vitamin D can cause autism. Randomized trials of vitamin D supplementation would be necessary to definitively determine this possibility. Researchers also noted that low vitamin D levels in pregnancy and early life are associated with other neurological conditions (e.g., attention-deficit/hyperactivity disorder, schizophrenia), so some of the same factors may be involved in all these cases.

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