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Study Suggests Mutations in Maternal Serotonin Genes Can Influence Children's ADHD Symptoms

By Andrea Anderson

NEW YORK (GenomeWeb News) – A genotyping study appearing in this month's issue of the Archives of General Psychiatry suggests a mother's serotonin levels might influence her child's risk of developing attention-deficit hyperactivity disorder symptoms down the road.

A Norwegian research team sequenced two genes — coding for the serotonin biosynthesis enzymes tryptophan hydroxylase 1 and 2 — in hundreds of individuals with or without ADHD, identifying eight mutations that apparently curtail the function of these enzymes, decreasing serotonin production.

When they tested dozens of families with such mutations, the researchers found that children show more ADHD-like symptoms when their mothers had TPH1 mutations than when their fathers carried the same sorts of mutations.

The study highlights the advantage of looking at maternal genotype as a possible predictor of child development, co-lead author Stefan Johansson, a biomedicine researcher at the University of Bergen, told GenomeWeb Daily News.

Past studies have pointed to possible serotonin involvement in ADHD and other psychiatric disorders, he explained, though there's no clear consensus on the role of serotonin-related genes in such conditions.

For the current study, the team focused on the TPH1 and TPH2 genes, which are thought to code for rate-limiting enzymes in serotonin synthesis, initially sequencing the two genes in 646 Norwegian individuals over 18 years old using the Sanger method.

From TPH1 sequence data for 457 individuals with ADHD and 187 unaffected controls and TPH2 sequence data for 459 cases and 179 controls, the researchers identified six missense mutations and one nonsense mutation in TPH1 and a pair of missense mutations in TPH2.

Given their results so far, the researchers estimate that roughly one percent of Norwegians carry one of the mutations to TPH1, which codes for the enzyme involved in 90 percent or more of the serotonin produced in peripheral tissues. Variants in the TPH2 gene seem to be even rarer, turning up in just 0.2 percent or so of the Norwegian population.

The team's findings suggest that all but one of the nine new and previously detected TPH1 and TPH2 changes lead to decreased serotonin levels, though Johansson noted that such predictions have yet to be confirmed in pregnant women, given the complications of measuring serotonin levels in vivo.

Nevertheless, the researchers' follow-up experiments in families with TPH1 mutation carriers further supported ties between maternal serotonin synthesis genes and ADHD symptoms in children.

When they specifically looked at 38 individuals carrying TPH1 mutations and 41 of their children, the team found that children born to women carrying such mutations scored 1.5 to 2.5 times higher on tests for ADHD symptoms than children who had fathers carrying these mutations.

That, in turn, suggests changes in serotonin levels in the mother's body might contribute to ADHD-related developmental processes, Johansson explained.

"Our data look like it's the influence from the mother that's important, especially when we're looking at TPH1," he said. "The expression is mostly TPH2 in the brain, so this is looking at how the periphery in the mother could influence the development of the brain of the fetus."

Even so, the researchers noted, the findings may not necessarily point to a role for the serotonin system in ADHD alone, but may reflect a broader influence for serotonin on a range of psychiatric conditions.

"We don't generally feel that [these are] particularly ADHD genes," Johansson said. "We look more at it as psychiatric disorder liability genes." Consequently, he noted, the team is interested in looking at other psychiatric disorders and may collaborate with other groups working on conditions such as autism, schizophrenia, and bipolar disorder.

The researchers also plan to continue searching for rare variants with ties to ADHD and related conditions. That will likely involve targeted gene sequencing in the near future, Johansson said, though he noted that such studies may eventually rely on broader approaches, such as exome sequencing.

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