Multi-scale systems genomics analysis predicts pathways, cell types, and drug targets involved in normative variation in peri-adolescent human cognition.
Shraddha PaiShirley HuiPhilipp WeberSoumil NarayanOwen WhitleyPeipei LiViviane LabrieJan BaumbachAnne L WheelerGary D BaiderPublished in: Cerebral cortex (New York, N.Y. : 1991) (2023)
An open challenge in human genetics is to better understand the systems-level impact of genotype variation on developmental cognition. To characterize the genetic underpinnings of peri-adolescent cognition, we performed genotype-phenotype and systems analysis for binarized accuracy in nine cognitive tasks from the Philadelphia Neurodevelopmental Cohort (~2,200 individuals of European continental ancestry aged 8-21 years). We report a region of genome-wide significance within the 3' end of the Fibulin-1 gene (P = 4.6 × 10-8), associated with accuracy in nonverbal reasoning, a heritable form of complex reasoning ability. Diffusion tensor imaging data from a subset of these participants identified a significant association of white matter fractional anisotropy with FBLN1 genotypes (P < 0.025); poor performers show an increase in the C and A allele for rs77601382 and rs5765534, respectively, which is associated with increased fractional anisotropy. Integration of published human brain-specific 'omic maps, including single-cell transcriptomes of the developing human brain, shows that FBLN1 demonstrates greatest expression in the fetal brain, as a marker of intermediate progenitor cells, demonstrates negligible expression in the adolescent and adult human brain, and demonstrates increased expression in the brain in schizophrenia. Collectively these findings warrant further study of this gene and genetic locus in cognition, neurodevelopment, and disease. Separately, genotype-pathway analysis identified an enrichment of variants associated with working memory accuracy in pathways related to development and to autonomic nervous system dysfunction. Top-ranking pathway genes include those genetically associated with diseases with working memory deficits, such as schizophrenia and Parkinson's disease. This work advances the "molecules-to-behavior" view of cognition and provides a framework for using systems-level organization of data for other biomedical domains.
Keyphrases
- working memory
- white matter
- genome wide
- single cell
- copy number
- poor prognosis
- mild cognitive impairment
- mental health
- young adults
- endothelial cells
- dna methylation
- transcranial direct current stimulation
- attention deficit hyperactivity disorder
- rna seq
- bipolar disorder
- emergency department
- randomized controlled trial
- acute lymphoblastic leukemia
- binding protein
- big data
- high throughput
- traumatic brain injury
- heart rate
- induced pluripotent stem cells
- heart rate variability
- machine learning
- brain injury
- electronic health record
- cell therapy
- childhood cancer
- drug induced
- artificial intelligence
- long non coding rna
- oxidative stress
- functional connectivity
- transcription factor