Pleiotropy and Cross-Disorder Genetics Among Psychiatric Disorders

Abstract

Genome-wide analyses of common and rare genetic variations have documented the heritability of major psychiatric disorders, established their highly polygenic genetic architecture, and identified hundreds of contributing variants. In recent years, these studies have illuminated another key feature of the genetic basis of psychiatric disorders: the important role and pervasive nature of pleiotropy. It is now clear that a substantial fraction of genetic influences on psychopathology transcend clinical diagnostic boundaries. In this review, we summarize evidence in psychiatry for pleiotropy at multiple levels of analysis: from overall genome-wide correlation to biological pathways and down to the level of individual loci. We examine underlying mechanisms of observed pleiotropy, including genetic effects on neurodevelopment, diverse actions of regulatory elements, mediated effects, and spurious associations of genomic variation with multiple phenotypes. We conclude with an exploration of the implications of pleiotropy for understanding the genetic basis of psychiatric disorders, informing nosology, and advancing the aims of precision psychiatry and genomic medicine.

Keywords: Cross-disorder; GWAS; Genetic correlation; Nosology; Pleiotropy; Precision psychiatry; Psychiatric genetics.

Figure 1.. Widespread pleiotropy among psychiatric disorders at different levels of genomic analysis.

Center panel: Pleiotropy has been estimated at the genome-wide scale as genetic correlation among psychiatric disorders. (e.g., r_g = 0.68 between SCZ and BD). Decomposition of the genetic correlation matrix for eight psychiatric disorders revealed a three-factor structure, comprising compulsive/perfectionistic behaviors (AN, OCD, and TS), mood and psychotic disorders (SCZ, BIP, MD), and early-onset NDDs (TS, ASD, ADHD, and MDD). Left panel: Multiple genes can form biological pathways, and individual pathways can cluster into more complicated networks. Analyses leveraging these aggregated genetic effects have identified specific pathways (e.g., calcium channel signaling and glutamate receptor signaling) enriched for loci affecting several psychiatric conditions. Right panel: Individual pleiotropic loci include copy number variants (CNVs) implicated in a range of NDDs (e.g., 22q11 deletions). Finally, a growing catalog of specific genes and single nucleotide variants have shown pleiotropic effects in common and rare variant association studies (e.g., association of CACNA1C with BD, SCZ, and ASD). SCZ: schizophrenia; BD: bipolar disorder; MDD: major depressive disorder; ASD: autism spectrum disorder; ADHD: attention-deficit/hyperactivity disorder; TS: Tourette syndrome; AN: anorexia nervosa; OCD: obsessive compulsive disorder

Figure 2.. Pleiotropic mechanisms underlying cross-phenotype associations.

We define three classses of pleiotropic mechanisms: biological pleiotropy, mediated pleiotropy, and spurious pleiotropy. (A) Biological pleiotropy include (a) single-gene pleiotropy where causal variants, residing in coding or non-coding regions, affects the function/activity/expression of a single gene that influences more than one trait; and (b) multi-gene regulatory pleiotropy where non-coding causal variants affect the expression of multiple genes simultaneously, each of which may underlie distinct traits. (B) Mediated pleiotropy refers to the situation in which a causal variant influences one trait which in turn causes phenotypic changes in a second trait. (C) Spurious pleiotropy describes situations when cross-trait associations occur due to various artefacts or limitations in study design.

Figure 3.. Examples of single-gene pleiotropy associated with psychiatric disorders.

A) Figure 3. Examples of single-gene pleiotropy associated with psychiatric disorders. A) Cell adhesion protein NRXN1 produces distinct protein isoforms, each may affect distinct brain circuits, behavioral systems, and psychiatric disorders. (B) Transcription factor TCF4 regulates more than 5% brain-expressed genes, many of which are key players in brain gene transcription, signaling, and neurodevelopment. (C) DCC is a master regulator that governs axon guidance during early neurodevelopment and mediation of mPFC dopamine connectivity during adolescence. (D) RBFOX1 encodes a cell-type-specific alternative splicing regulator that plays an essential role for neural development and excitability.