Genetic data reveals how brain structure contributes to autism and attention disorders

Differences in the physical shape and wiring of the brain can directly contribute to the development of attention and social disorders. A recent genetics study mapped how the size of specific brain folds and the organization of brain wiring alter the risk of developing autism and attention deficit hyperactivity disorder. The findings were published in the journal Progress in Neuropsychopharmacology & Biological Psychiatry.

Autism spectrum disorder and attention deficit hyperactivity disorder are developmental conditions that can persist throughout a person’s life. They affect how individuals process information, regulate their attention spans, and engage in social interactions. People dealing with these neurological differences often face elevated emotional burdens and adverse health outcomes compared to their peers.

Medical professionals have utilized brain scans to study these populations for decades. Those imaging tests frequently show that neurodivergent individuals have slightly different brain structures compared to typically developing people. However, simple observational brain scans cannot tell investigators which event happened first.

A difference in brain structure might cause the condition, or living with the condition might slowly shape the physical brain as a person grows. It is also completely plausible that a third unrelated environmental factor causes both the brain changes and the behavioral symptoms.

To solve this timing puzzle, researchers rely on massive genetic datasets. Yilu Zhao, Yamin Zhang, and Tao Li, researchers at Zhejiang University in China, designed a study to systematically test whether differences in brain structure actually dictate the onset of these neurodevelopmental conditions.

The research team focused their investigation on two primary physical components of the human brain. Gray matter consists of the tiny bodies of nerve cells, where the actual processing of sensory information takes place. This tissue covers the exterior of the brain in deep folds and ridges, maximizing the total processing surface area within the confined space of the human skull.

White matter lies beneath this outer processing shell. It is made up of axons, which are long, insulated fibers that stretch between distant nerve cell bodies. These biological cables act like communication highways, allowing different specialized regions of gray matter to coordinate their electrical activity.

To figure out how these tissues relate to developmental disorders, the investigators used an approach called Mendelian randomization. When medical experts want to know if a medication works, they run a randomized clinical trial, assigning patients to receive either the active drug or a placebo. Mendelian randomization uses a similar logic, but it uses the natural genetic shuffling that happens before birth.

Humans inherit natural variations in their genetic code from their parents. Some of these tiny genetic variations reliably dictate physical characteristics of the brain. By looking at huge population databases, scientists can isolate the exact genetic markers that result in slightly thicker brain folds or highly organized white matter fiber bundles.

Analysts can then check if those exact same genetic blueprints are overly present in populations diagnosed with neurological conditions. If the genes that build a specific brain shape also track perfectly with a diagnosis, the researchers can deduce a sequence of events. The genes dictate the brain architecture, and the architecture acts as the biological precursor to the behavioral symptoms.

Following this method, Zhao and colleagues gathered genetic profiles for tens of thousands of individuals. They cross-referenced genes known to alter gray matter and white matter dimensions against separate databases containing DNA from people diagnosed with either autism or attention deficit hyperactivity disorder. They found specific regions in the frontal lobe of the brain that act as direct structural contributors to these conditions.

The frontal lobe is the large region situated behind the forehead, heavily involved in decision-making, social behavior, and attention span. For attention deficit hyperactivity disorder, the team found that having an increased surface area in the superior frontal gyrus raised the risk of developing the condition. The superior frontal gyrus is a strip of brain tissue near the top of the frontal lobe.

Previous imaging studies have linked the superior frontal gyrus to executive functioning and the ability to suppress impulsive responses. These are common cognitive challenges for individuals with attention deficit hyperactivity disorder. Finding that an overgrowth of surface area in this specific region causes the disorder fits well with behavioral observations, suggesting normal tissue maturation is altered.

The researchers identified a vastly different pattern for autism spectrum disorder. They looked closely at the orbital frontal gyrus, a region located just resting above the eyes. This neural area processes incoming sensory information and helps interpret the emotional states of other people.

The genetic analysis showed that a larger surface area in the orbital frontal gyrus essentially protects against autism risk. Individuals possessing genetic markers for a more expansive orbital frontal gyrus were less likely to be diagnosed with autism. A larger processing area in this region seemingly provides a buffer against the social and communicative challenges associated with the condition.

The research team then transitioned to exploring the brain’s internal white matter connectivity. They analyzed a tissue property that describes the physical complexity and orientation of the nerve fibers crossing through the deep brain. Highly organized structural pathways are essential for efficiently integrating thoughts and senses across long distances.

For attention deficit hyperactivity disorder, an altered structural connection called the inferior fronto-occipital fasciculus emerged as a contributing factor. This pathway is a bundle of fibers connecting the visual centers at the back of the brain to the language processing centers at the front. The data indicated that the developmental organization of this visual-to-frontal relay directly influences the risk of the attention disorder.

For autism risk, a separate white matter tract was implicated. The investigators found that physical variations in a deep brain intersection called the internal capsule contributed to autism diagnoses. Reduced structural integrity in the specific pathway carrying visual sensory data to the cortex increased the likelihood of a child being diagnosed with autism.

The scientists also ran their mathematical models in reverse to scan for opposite connections. They wanted to know if inheriting genetic markers for attention deficit hyperactivity disorder or autism eventually caused the brain structures to physically morph over time. The results for this reverse progression were not statistically significant. The physical brain shapes appear to drive the behavioral conditions, rather than the conditions driving the architecture.

A brain’s physical architecture is only one part of the wider puzzle. The way those physical structures actively talk to one another represents the brain’s functional network. Magnetic resonance imaging can capture this live activity by measuring tiny changes in blood oxygen levels as different tissues fire electrical signals.

The Zhejiang University team ran an additional test using live functional imaging data to see how physical shapes translated into behavioral symptoms. They found that resting brain connectivity acts as a functional bridge. For example, an expanded surface area in the superior frontal gyrus alters how that frontal tissue routinely communicates with areas controlling physical movement.

This altered real-time communication then leads to the recognizable physical and behavioral symptoms of an attention disorder. It is akin to a city’s road network dictating its daily traffic jams. An abnormally wide road structure permanently changes where cars tend to drive, and that altered traffic flow ultimately creates the observable congestion.

When dividing their data by demographic details, the scientists noticed distinct trends. For attention deficit hyperactivity disorder, the structural causes were highly apparent in childhood-onset cases. However, when the researchers looked at data from individuals diagnosed later in adulthood, these specific anatomical causes were not statistically significant.

When analyzing the genetic information by sex, the team found that the white matter link to attention disorders was strong in boys but absent in girls. This physiological difference aligns with worldwide clinical observations, as males are historically diagnosed with attention disorders at much higher rates than females. Conversely, the structural shape factors linked to autism risk were universally present in both male and female genetic profiles.

While the genetics approach offers strong evidence for causality, the study authors acknowledged a few data limitations. The massive DNA databases used in the analysis were primarily sourced from individuals of European ancestry. This lack of genetic diversity means the anatomical pathways identified might not perfectly represent the global population.

Future research efforts will need to incorporate genetic profiles from a wider range of global ethnic backgrounds to ensure the results are robust. Additional large-scale genetic tracing projects could also test for similar structural drivers in other developmental variants, such as specific learning variations or communication delays.

The study, “Causal relationships between ADHD, ASD and brain structure: A mendelian randomization study,” was authored by Yilu Zhao, Yamin Zhang, and Tao Li.