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From Molecular Insights to Patient Stratification for Neurological and Psychiatric Disorders Proceedings of a Workshop (2022) / Chapter Skim
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4 Leveraging New Methodologies to Interpret Genetic Data in Neurological and Psychiatric Disorders
Pages 27-36

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From page 27...
... . • Gene network analysis can help define the molecular p ­ athology of psychiatric disorders and enable cross-disorder compari sons, genetic enrichment analyses, and the assessment of reli ability and relevance of in vitro models (Geschwind)
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From page 28...
... Finucane said she thinks a very simple pattern of variants underlies this complex pattern of association. Statistical fine mapping enables recovery of simple causal structures from complex association data, she said.
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From page 29...
... Consortium6 demonstrated in a paper published in medRxiv that 95 percent of patients carry many genetic variants with very low effect sizes, while a minority of patients express rare mutations that increase the risk substantially.7 To sort out complexity in the 95 percent of patients with low-effect size variants, Hjerling-Leffler focuses on individual cell types in the brain using single-cell transcriptomics, which informs both genetics and pathol 2  Made available in preprint format. To learn more, see https://www.medrxiv.org/content/ 10.1101/2021.09.03.21262975v1 (accessed December 8, 2021)
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From page 30...
... FUNCTIONAL EFFECTS OF CODING VARIATION Determining how genetic variation affects function has been an expanding problem in clinical genetics, said Lea Starita, assistant professor of genome sciences at University of Washington and co-director of the advanced technology lab at the Brotman Baty Institute for Precision Medicine. The conventional wisdom in the field was that as sequencing became more widely used, "we were going to sequence our way out of this problem by linking more variants to disease," she said.
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From page 31...
... to sequencing could enable analysis of thousands of variants simultaneously, she said. Starita and colleagues are using a technique called saturation genome editing to insert all possible single-nucleotide variants into key regions of the BRCA1 gene.
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From page 32...
... Among these is the difficulty of pinpointing the actual causal genes within the genetic risk loci identified, she said. ­Strategies she described to address this challenge include functional annota tion, where all variants in a risk locus are annotated with biological infor mation gleaned through several tools; statistical fine mapping described earlier by Finucane; and local genetic correlation analysis where one looks to see whether the genetic variant of interest is also associated with other traits.
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From page 33...
... "The more specific our hypotheses are, the better the functional follow-up experiments can be," she said. REGULATORY MAPS, GENE NETWORKS, AND HIGH-THROUGHPUT FUNCTIONAL VALIDATION As discussed by previous speakers, major challenges facing genetic s­ tudies of disease include determining which variants are causal, what genes they regulate, and the functional consequence of those variants, said Daniel Geschwind, professor of neurology, psychiatry, and human g­ enetics and director of the Institute for Precision Health at the University of California, Los Angeles.
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From page 34...
... He and others have shown that network structure is robust and reproducible; that a gene's network position is biologically meaningful; and that network structure serves as a basis for biologically meaningful insights. Moreover, he said, gene network analysis provides an organizing framework to define the molecular pathology of psychiatric disorders, serves as a quantitative p ­ henotype for cross-disorder comparisons, enables genetic enrichment analyses, and permits the assessment of reliability and relevance of in vitro models.
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From page 35...
... FIGURE 4-2  Reverse engineering of disease networks from large-scale gene perturbation data. Reverse engineering experiments can be used to rebuild original networks, identify drugs and drivers, and test them experimentally.
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From page 36...
... Geschwind added that while in vitro phenotypes such as cell death or axon growth may be relevant for disorders such as dementia, much less is known about the appropriate in vitro phenotype for autism, schizophrenia, depression, and other neuropsychiatric disorders. "Once we know a little bit more about what we're trying to preserve or enhance, like blocking cell death, I think it will make these in vitro assays much more powerful," he said.
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Key Terms

  • fine mapping
  • psychiatric disorders
  • accessed december
  • cell types
  • statistical fine

  • cell death
  • genetic data
  • neuropsychiatric disorders
  • association data
  • reverse engineering

  • specific cell
  • genetic variation
  • single cell
  • interpreting genetic
  • genetic enrichment

  • gene network
  • cell type
  • network structure
  • network biology
  • causal variants

  • network analysis
  • genome editing
  • complex trait
  • massively parallel
  • saturation genome

  • functional data
  • complex association
  • clinical genetics
  • biologically meaningful
  • mechanistic insight


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