Certain mutations in MECP2, a protein that modulates transcription by binding methylated CpG dinucleotides, cause Rett syndrome (Amir et al., 1999) and are associated with other neurodevelopmental disorders, including autism (Loat et al., 2008). Abnormal head growth characterizes both conditions, making MECP2 a promising candidate for associating common gene variants with brain structure changes, Joyner said. “The hypothesis was that variants of the same genes that cause rare diseases might be causing normal variation in brain structure measures.”

To address this possibility, Joyner and Schork teamed up with brain imaging expert Anders Dale at UCSD, psychiatrist Ole Andreassen at the University of Oslo, Norway, and other researchers at both institutions. They started by analyzing genomics and brain imaging data from 289 healthy and psychiatric patients from an ongoing Thematic Organized Psychosis (TOP) project in Norway. Among males, the minor allele of five out of the 11 single-nucleotide polymorphisms (SNPs) tested was found to associate with reductions in three of four measures of brain structure—intracranial volume, parenchymal volume, cortical surface area, and mean cortical thickness.

The researchers were able to replicate the top two SNPs from the Norwegian study in an independent population—655 participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI), an ongoing North American project funded by the National Institutes of Health with industry support (see ARF ADNI series). Some ADNI volunteers were healthy (n = 187), while others had dementia (322 with mild cognitive impairment, 146 with AD). In both populations, gene variations did not appear linked to clinical diagnosis, quelling suspicion that disease elements may be driving the observed genetic associations.

Replication of the TOP findings in a completely different disease cohort (ADNI) was “one of the most important aspects of this paper,” Joyner said. “It's powerful evidence of a real effect.” Several studies had suggested that common polymorphisms of other genes—for example, brain-derived neurotrophic factor (Varnäs et al., 2008)—are associated with differences in brain size. However, the MECP2 study is the first replicated example.

Curiously, only males showed the association between the MECP2 SNPs and brain structure. This is likely because MECP2 is on the X chromosome, so females carrying a MECP2 mutation still have a backup allele that may partially compensate for the defective chromosome. “This may play into why autism is so much more prevalent in males,” Joyner said. “It is something we will be exploring.”

To that end, Joyner is sequencing the MECP2 gene in autism samples for which brain imaging data are also available. Previous efforts to sequence MECP2 in autistic patients have focused on small areas such as exons and the 3’ untranslated region. “But this gene has very subtle regulation. It’s regulated by many elements inside and outside the gene,” Joyner said. “Our hypothesis is that this gene may be causing autism in many more cases than is known, because these regulatory elements have not yet been sequenced.”—Esther Landhuis.

Reference:
Joyner AH, Roddey JC, Bloss CS, Bakken TE, Rimol LM, Melle I, Agartz I, Djurovic S, Topol EJ, Schork NJ, Andreassen OA, Dale AM. A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations. PNAS Early Edition. August 2009. Abstract