Brain disorders are multifactorial complex phenotypes influenced by hundreds of genetic variants, each with a subtle effect, complicating their identification. While often individually elusive, these variants collectively can impose substantial risk. We developed tools like pleioFDR and MOSTest to improve the discovery of genetic variants in complex phenotypes, enhancing our understanding of the genetic landscape in brain disorders and related neuroimaging traits.
The analysis of large-scale genetic, neuroimaging and multiomics data presents challenges, such as managing high-dimensionality and complex correlations, which can lead to overfitting and reduced generalizability. We have created methods like FEMA and MiXeR to effectively analyze these intricate data modalities, resulting in more accurate models of genetic landscapes in brain disorders. Understanding genomics, neuroimaging and multiomics biomarkers, and combining this knowledge with clinical and health registry data, aids in developing multimodal prediction tools. Our work includes applications across neurodevelopmental, psychiatric and neuropsychiatric diseases. For example, in Alzheimer's disease, we emphasize early detection and differential diagnosis, where clinical relevance is anticipated in the near future.
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Frei O, Holland D, Smeland OB, Shadrin AA, Fan CC, Maeland S, O'Connell KS, Wang Y, Djurovic S, Thompson WK, Andreassen OA, Dale AM. Bivariate causal mixture model quantifies polygenic overlap between complex traits beyond genetic correlation. Nat Commun. 2019 Jun 3;10(1):2417. doi: 10.1038/s41467-019-10310-0.
Frei O, Hindley G, Shadrin AA, van der Meer D, Akdeniz BC, Hagen E, Cheng W, O'Connell KS, Bahrami S, Parker N, Smeland OB, Holland D; Schizophrenia Working Group of the Psychiatric Genomics Consortium; de Leeuw C, Posthuma D, Andreassen OA, Dale AM. Improved functional mapping of complex trait heritability with GSA-MiXeR implicates biologically specific gene sets. Nat Genet. 2024 Jun;56(6):1310-1318. doi: 10.1038/s41588-024-01771-1.
van der Meer D, Frei O, Kaufmann T, Shadrin AA, Devor A, Smeland OB, Thompson WK, Fan CC, Holland D, Westlye LT, Andreassen OA, Dale AM. Understanding the genetic determinants of the brain with MOSTest. Nat Commun. 2020 Jul 14;11(1):3512. doi: 10.1038/s41467-020-17368-1.
Akdeniz BC, Frei O, Shadrin A, Vetrov D, Kropotov D, Hovig E, Andreassen OA, Dale AM. Finemap-MiXeR: A variational Bayesian approach for genetic finemapping. PLoS Genet. 2024 Aug 15;20(8):e1011372. doi: 10.1371/journal.pgen.1011372.