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Genetics and genomics of psychiatric disease - PubMed

  • ️Thu Jan 01 2015

Review

Genetics and genomics of psychiatric disease

Daniel H Geschwind et al. Science. 2015.

Abstract

Large-scale genomic investigations have just begun to illuminate the molecular genetic contributions to major psychiatric illnesses, ranging from small-effect-size common variants to larger-effect-size rare mutations. The findings provide causal anchors from which to understand their neurobiological basis. Although these studies represent enormous success, they highlight major challenges reflected in the heterogeneity and polygenicity of all of these conditions and the difficulty of connecting multiple levels of molecular, cellular, and circuit functions to complex human behavior. Nevertheless, these advances place us on the threshold of a new frontier in the pathophysiological understanding, diagnosis, and treatment of psychiatric disease.

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Figures

Fig. 1
Fig. 1. Summary of genetic analyses performed on 13 psychiatric disorders

(A) Highest lifetime (point for ASD) prevalence in percentages. The discontinuous bar in phobias represents the range in different forms. (B) Heritability estimates; bars, standard error (SE). (C) SNP-based heritability estimates; bars, SE. (D) Number of genome-wide significant loci. The x axis is discontinuous because of the large difference of associated loci between disorders. (E) The number of associated structural variants (SVs) that either reach genome-wide significance or have been replicated with P ≤ 0.01 in another study. (F) The y axis shows associated GWAS loci (blue) and SVs (green) by the number of cases (x axis) in the largest study for that disorder. The number of cases in the largest study for GWAS (D) and SV studies (E) is reported next to each disorder. Abbreviations are as follows: ANX, any anxiety disorder; AAD, alcohol abuse disorder; MDD, major depressive disorder; PHO, = any phobia; CON, conduct disorders; PTSD, post traumatic stress disorder; EAT, eating disorders; TS, Tourette syndrome. The order of disorders and their color coding are maintained throughout the bar plots. See table S1 for underlying data and references amalgamated from many sources.

Fig. 2
Fig. 2. Pairwise genetic correlations for four psychiatric disorders

Plotted on the vertical axis are BPD, SCZ, MDD, and ASD (2). The horizontal colored lines mark the mean of the genetic correlation based on SNP sharing for each pair of illnesses, and the dotted vertical colored lines are the SEs of the estimates. Data are from Maier et al. (69).

Fig. 3
Fig. 3. Heterogeneous genetic risk factors converge in biological networks

Different study designs, such as trios, multiplex affected families, or case-control (shown at far left) identify different forms of genetic risk in cases (the arrow size indicates the relative effect size). By integrating these data with biological network data, one can assess in a genome-wide manner whether disease-associated risk variants are enriched in specific biological networks (46). Here, for illustration, we depict rare de novo variants associated with ASD, enriched in the yellow module. The function of this module of co-regulated genes can be further annotated using gene ontology, which implicates these large-effect ASD-associated variants in chromatin remodeling, transcriptional regulation, and neurogenesis. Networks can be subsequently mapped onto developmental time points, brain regions, circuits, or cells.

Fig. 4
Fig. 4. Refining diagnoses based on genetic susceptibility

Clinical disorders (abbreviations are as in Fig. 1) and their overlap, represented by the big circles. The smaller dots within each circle represent contributing genetic or environmental risk factors. Once genetic risk is defined in population studies, it can be used to define factors underlying disease risk in individuals, identifying distinct (or overlapping) entities, two of which are represented by the elongated ovals at the bottom, grounded in causal mechanistic understanding. These subtypes should more clearly inform prognosis and treatment than do current categorical disease entities. The sizes of the dots within the circles represent the relative effect sizes of variants.

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