The Brain Imaging Genetics (BIG) project

The Brain Imaging Genetics (BIG) project in Nijmegen, which forms the basis for the Cognomics initiative, contains data from more than 3,500 healthy individuals. Several local and external research groups have made use of these data, investigating the complex links between genes, brain structure and function, and cognition.

ENIGMA

With the data from BIG, we participate in various GWAS meta-analyses of brain structure through the ENIGMA consortium, of which we are co-founders and members of the steering committee. ENGIMA has identified hundreds of genetic variants involved in the architecture of the human cerebral cortex.

Psychiatry

Investigating the role of known risk factors for psychiatric disease in our BIG cohort of healthy volunteers, we found that risk alleles for Alzheimer’s disease affect hippocampus and entorhinal cortex volumes, and that the psychosis risk gene CACNA1C alters brainstem volume.

On the other hand, we observed no effects of schizophrenia risk genes MIR137, TCF4, and ZNF804A or genetic risk scores for schizophrenia on macroscopic brain structure. These results suggest that, by themselves, these genetic risk factors are not enough to induce brain structural changes in healthy volunteers. Structural changes would perhaps only arise in combination with additional schizophrenia risk factors (e.g., infection, trauma, rare genetic variants, or gene-gene interactions).

Language and brain asymmetry

We used the BIG sample to study the effects of language and reading related genetic variants on brain structure. There was significant multivariate association of rs5995177 (RBFOX2) with cortical thickness, driven by effects on left postcentral parietal gyrus, right middle temporal gyrus, right inferior frontal gyus, and superior temporal gyrus bilaterally. The prior reported association of rs5995177 with reading/language performance could thus potentially be mediated by reduced thickness in the above associated cortical regions.

Together with the ENIGMA Consortium we performed the largest-ever analysis of cerebral cortical asymmetry and its variability across 17,141 healthy individuals. Results revealed widespread asymmetries at both hemispheric and regional levels, with a generally thicker cortex but smaller surface area in the left hemisphere relative to the right. Variability in brain asymmetry was related to sex, age, and intracranial volume, but not to handedness. Asymmetries showed significant, replicable heritability.

Memory and emotion

Our studies in BIG reveal a complex interaction between the BDNF gene and aversive early life events on subgenual anterior cingulate cortex volume, a brain structure affected in major depression. The interaction between this polymorphism and early life adversity is also causing a negative memory bias, a cognitive hallmark of depression, known to be critical for disease onset and maintenance.

Less positive memory bias was also found for individuals with the SS genotype of the 5-HTTLPR polymorphism who had experienced interpersonal childhood traumatic events. A complementary analysis indicated that the S'-allele was associated with smaller hippocampal volume in women, independent of childhood adversity. Men only had smaller hippocampi if they both carried the risk allele and experienced severe childhood adversity.