Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

In the paper

“Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders.”

In the paper

“Within these 136 loci, multi-SNP-based conditional analysis (Yang et al., 2012) identified 10 additional SNPs with independent associations, resulting in a total of 146 independent lead SNPs”

What the sources say

• Not checked yetcites Yang et al., 2012 source

In the paper

“Enrichment analyses using the genes preferentially expressed in specific cortical regions suggested that pleiotropic loci were over-represented among genes expressed in the frontal cortex, while non-pleiotropic loci were enriched in the occipital cortex (FDR q <0.05; Figure 5C).”

In the paper

“two loci between SCZ and ASD (rs9329221, rs2921036)”

In the paper

“Eleven of the 23 lead SNPs map to the intron of a protein-coding gene, and seven additional lead SNPs had at least one protein-coding gene within 100 kb.”

In the paper

“Gene expression data indicate that DCC expression peaks during early prenatal development (Figure S3).”

In the paper

“More than 41% of the genes associated with our genome-wide significant loci, both pleiotropic and non-pleiotropic, were intolerant of loss of function mutations (pLI score R 0.9); this is highly unlikely to occur by chance (Fisher's exact p = 4.90 3 10 8 ).”

In the paper

“The 109 pleiotropic risk loci were enriched for genes involved in neurogenesis (gene-set enrichment p = 9.67 3 10 6 ), regulation of nervous system development (p = 3.41 3 10 5 ), and neuron differentiation (p = 3.30 3 10 5 )”

In the paper

“Overall, they showed significant enrichment of genes expressed in the brain ( beta = 0.123, SE = 0.0109, enrichment p = 1.22 3 10 29 ) and pituitary ( beta = 0.0916, SE = 0.0136, p = 8.74 3 10 12 ), but not in the other Genotype-Tissue Expression (GTEx) tissues.”

In the paper

“Expression levels were associated with the degree of pleiotropy, with the pleiotropy > 2 group showing higher gene expression than either the pleiotropy = 2 group (t test p < 2.10 3 10 4 ) or non-pleiotropic risk loci (t test p < 2.2 3 10 16 ).”

In the paper

“The other disorders, ADHD, TS, OCD, and AN featured associations in 16%, 14%, 11%, and 7% of the pleiotropic loci, respectively.”

In the paper

“Neither did we find differences between disorder-specific lead SNPs and pleiotropic SNPs with respect to their minor allele frequencies, average heterozygosity, or predicted allele ages (Kiezun et al., 2013).”

What the sources say

• Not checked yetcites Kiezun et al., 2013 source

In the paper

“Pleiotropic and non-pleiotropic SNPs also did not differ in terms of the distance to nearest genes, distance to splicing sites, chromosome compositions, and predicted functional consequences of non-coding regulatory elements.”

In the paper

“Cell-type-specific analysis indicated that genes implicated in pleiotropic loci were mainly expressed in neurons (FDR q <0.05) but not in glial cell types.”

In the paper

“and KDM7A (encoding Lysine Demethylase 7A)”

In the paper

“Pleiotropic risk loci also showed enrichment of genes involved in specific neurotransmitter-related pathwaysglutamate receptor signaling (p = 2.45 3 10 6 ) and voltagegated calcium channel complex (p = 5.72 3 10 4 )”

In the paper

“Of the single-disorderspecific loci, 81% and 16% were associated with SCZ and MD, respectively.”

In the paper

“Of the 109 pleiotropic loci, 76 were identified in the GWAS of individual disorders, while the remaining 33 are novel.”

In the paper

“Of the 109 pleiotropic loci, 83% and 72% involved SCZ and BIP, respectively.”

In the paper

“In contrast to DCC , however, developmental gene-expression of RBFOX1 showed gradually increasing gene expression throughout the prenatal period (Figure S3).”

In the paper

“average expression of genes related to pleiotropic loci peaked in the second trimester and remained overexpressed throughout the lifespan.”

In the paper

“Finally, we found that genes associated with multiple psychiatric disorders are disproportionately associated with biological pathways related to neurodevelopment and exhibit distinctive gene expression patterns, with enhanced expression beginning in the second prenatal trimester and persistently elevated expression relative to less pleiotropic genes.”

In the paper

“we identified 146 LD-independent lead SNPs associated with at least one disorder, including 35 novel loci.”

In the paper

“Consistent with prior research (Brainstorm Consortium et al., 2018; CrossDisorder Group of the Psychiatric Genomics Consortium, 2013), we found substantial pairwise genetic correlations across child- and adult-onset disorders and extended these findings by demonstrating clusters of genetically-related disorders.”

What the sources say

• Not checked yetcites Brainstorm Consortium et al., 2018
• Not checked yetcites CrossDisorder Group of the Psychiatric Genomics Consortium, 2013

In the paper

“Of these, 109 loci were found to affect two or more disorders, although characterization of this pleiotropy is partly dependent on per-disorder sample size.”

In the paper

“We also identified 109 genomic loci with pleiotropic effects, of which 33 had not previously been associated with any of the individual disorders.”

In the paper

“These pleiotropic genes, on average, begin to come online by the second trimester of fetal development and exhibit differentially high expression thereafter.”

In the paper

“In general, as power increased, so did the number of identified SNPs.”

In the paper

“A model that included additional negative cross-loadings provided similar fit to the data and highly similar correlations across the genetic factors.”

In the paper

“Note that, in both the WLS and the ML solution, the standard errors are smaller for the loadings involving the better-powered GWAS phenotypes, as we would expect.”

In the paper

“Despite variation in magnitude, significant genetic correlations were apparent for most pairs of disorders, suggesting a complex, higher-order genetic structure underlying psychopathology”

In the paper

“Psychiatric disorders are highly polygenic, with a large proportion of heritability contributed by common variation.”

What the sources say

• Not checked yetcites Sullivan et al., 2018 source

In the paper

“Many risk loci have emerged from genome-wide association studies (GWAS) of, amongothers, schizophrenia (SCZ), bipolar disorder (BIP), major depression (MD), and attention-deficit/hyperactivity disorder (ADHD) from the Psychiatric Genomics Consortium (PGC) and other efforts”

What the sources say

• Not checked yetcites Sullivan et al., 2018 source

In the paper

“in a sample comprising 33,332 cases and 27,888 controls”

What the sources say

• Not checked yetcites CrossDisorder Group of the Psychiatric Genomics Consortium, 2013

In the paper

“The factor structure described above is based on average effects across the genome, but does not address more finegrained cross-disorder effects at the level of genomic regions or individual loci.”

In the paper

“Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci.”

In the paper

“All study participants were of self-identified European ancestry, which was supported by principal component analysis of genome-wide data.”

In the paper

“As a member of the NOX family genes that encode subunits of NADPH oxidase, NOX4 is a major source of superoxide production in human brain and a promoter of neural stem cell growth (Kuroda et al., 2014; Topchiy et al., 2013).”

What the sources say

• Not checked yetcites Kuroda et al., 2014 source
• Not checked yetcites Topchiy et al., 2013 source

In the paper

“BRAF , which contributes to the MAP kinase signal transduction pathway and plays a role in postsynaptic responses of hippocampal neurons (Grantyn and Grantyn, 1973)”

What the sources say

• Not checked yetcites Grantyn and Grantyn, 1973 source

In the paper

“The signal in our meta-analysis colocalizes with brain eQTLs for DCC (eQTL association FDR q = 2.27 3 10 5 ), supporting DCC as a plausible candidate gene”

In the paper

“KDM7A (encoding Lysine Demethylase 7A), which plays a central role in the nervous system and midbrain development (Horton et al., 2010; Qi et al., 2010; Tsukada et al., 2010).”

What the sources say

• Not checked yetcites Horton et al., 2010 source
• Not checked yetcites Qi et al., 2010
• Not checked yetcites Tsukada et al., 2010 source

In the paper

“The product of DCC plays a key role in guiding axonal growth during neurodevelopment and serves as a master regulator of midline crossing and white matter projections (Bendriem and Ross, 2017).”

What the sources say

• Not checked yetcites Bendriem and Ross, 2017 source

In the paper

“RBFOX1 (also called A2BP1 ) encodes a splicing regulator mainly expressed in neurons and known to target several genes important to neuronal development, including NMDA receptor 1 and voltage-gated calcium channels (Gandal et al., 2018; Gehman et al., 2011; Hamada et al., 2015).”

What the sources say

• Not checked yetcites Gandal et al., 2018 source
• Not checked yetcites Gehman et al., 2011 source
• Not checked yetcites Hamada et al., 2015 source

In the paper

“Previous studies of model organisms using gene knock-out experiments suggested that pleiotropic risk loci may undergo stronger selection than non-pleiotropic loci (Hill and Zhang, 2012).”

What the sources say

• Not checked yetcites Hill and Zhang, 2012 source

In the paper

“and has been previously associated with both MD and neuroticism (Turley et al., 2018; Wray et al., 2018).”

What the sources say

• Not checked yetcites Turley et al., 2018 source
• Not checked yetcites Wray et al., 2018 source

In the paper

“These results are based on average expression profiles, and not all individual gene expression patterns follow this pattern.”

In the paper

“Overall, these results indicate a substantial pairwise genetic correlation between multiple disorders along with a higher-level genetic structure that point to broader domains underlying genetic risk to psychopathology.”

In the paper

“the method we applied to detect cross-phenotype association, which combines an all-subsets fixed-effects GWAS meta-analysis with a Bayesian method for evaluating the best-fit configuration of genotype-phenotype associations, is one of several approaches (Solovieff et al., 2013).”

What the sources say

• Not checked yetcites Solovieff et al., 2013 source

In the paper

“Prior studies showed that DCC is a master regulator of axon guidance (through its interactions with netrin-1 and draxin (Liu et al., 2018).”

What the sources say

• Not checked yetcites Liu et al., 2018 source

In the paper

“Thus, some of the ''non-pleiotropic'' loci may have additional effects on psychiatric phenotypes that were not included in our meta-analysis and/or on non-psychiatric phenotypes.”

In the paper

“Standardized genomic inflation factor ( l 1000) for the meta-analysis result was close to one. LDSC intercept was substantially less than l GC (0.79 versus 1.55), suggesting that the increase in mean c 2 statistics in the cross-disorder meta-analysis is mainly due to polygenicity and not due to stratification or other confounding biases.”

In the paper

“As shown in Data S1 .4, the results were consistent with those from the primary analysis reported in the main text that is based on a Weighted Least-squares (WLS) estimator, which does take into account the differing precisions of the genetic covariance estimates. Specifically, the nontrivial standardized factor loadings of MD on two of the three factors is evident in both the WLS and ML solutions”

In the paper

“It should be noted that the average expression values of each gene set correspond to representative expression patterns of the disease risk genes, so individual genes may behave differently.”

In the paper

“while sample size will affect the precision of a genetic correlation estimate (ie standard error) it should not affect the magnitude of the estimate itself (Bulik-Sullivan et al., 2015).”

What the sources say

• Not checked yetcites Bulik-Sullivan et al., 2015 source

In the paper

“however, these estimates are generally consistent with previously reported ones when sample sizes are much smaller (except for ASD) (Brainstorm Consortium et al., 2018) (Cross-Disorder Group of the Psychiatric Genomics et al., 2013)”

What the sources say

• Not checked yetcites Brainstorm Consortium et al., 2018
• Not checked yetcites Cross-Disorder Group of the Psychiatric Genomics et al., 2013