Genes, cells, and schizophrenia

To understand the biological and genetic basis of common, complex disease, two challenges today are (i) to identify the functional alleles and biological mechanisms underlying genetic associations with disease risk; and (ii) to understand how these genes and alleles affect the biology of specific cell populations in complex tissues. Our lab’s work focuses on these challenges. I will talk on Friday about two such projects in our work to understand the biological basis of neuropsychiatric disorders.

The strongest genetic influence on schizophrenia at a population level involves the disorder’s association with common SNPs in the major histocompatibility complex (MHC) locus on chromosome 6. Though the MHC association is the earliest and strongest genetic signal in schizophrenia, it has been seen as presenting an intractable fine-mapping problem because the complex association signal does not track with patterns of linkage disequilibrium around any known variants. I will describe our work to understand this genetic signal and the functional alleles underlying it. The work has led us to surprising insights about both genetic architecture and a neuro-immune mechanism in schizophrenia.

Ultimately we must understand this and other genetic effects in terms of how genome variation shapes the biology of specific cell populations within complex tissues. A challenge in studying the brain and other complex tissues is that they contain tens to hundreds of cell types and cell states, each of which utilizes the genome in distinct ways. I will describe our lab’s work to develop Drop-seq, a new technology for simultaneously analyzing genome-wide gene expression in tens of thousands of individual cells. I will discuss ways that we are applying Drop-seq to better understand how diverse cell populations utilize their genomes and are affected by genetic variation.