Additional file 1 of Autosomal genetic control of human gene expression does not differ across the sexes

Supplementary figures. (PDF 971 kb

mediation_summary_stats

summary file for n=781 trans-eQTL associations (p<0.0000001) with a potentially mediating cis-transcrip

cis_eQTLs_P<0.05

cis-eQTLs with p<0.0

trans_eQTLs_P<0.0001

trans-eQTLs with p<0.000

Strong evidence of <i>cis</i>-mediation is detected only when the lead <i>trans</i>-eSNP and the lead <i>cis</i>-eSNP for the mediating transcript are in strong LD.

<p>The proportion of a <i>trans</i>-eQTL mediated by a <i>cis</i>-transcript (i.e., the “mediation proportion) is plotted against the negative log₁₀ of the Sobel P value for mediation for “FDR-significant” <i>trans</i>-eQTLs (panel A) and for “suggestive” <i>trans</i>-eQTLs (panel B). The plot is truncated at a Sobel P value of 10⁻¹⁶. Two outliers with a “mediation proportion”>2 have been excluded from panel A.</p

Percent of <i>trans</i>-eQTL signals¹ showing evidence of <i>cis</i>-mediation according to LD between the lead <i>trans</i>-eSNP and the lead <i>cis</i>-eSNP and the P-threshold for <i>trans</i>-eQTL analysis.

1<p>The <i>trans</i>-eQTL signals presented are probe-level signals.</p>2<p>r² is a measure of LD between the lead SNP for the <i>trans</i>-eQTL signal and the lead <i>cis</i>-eSNP for the potentially mediating transcript (i.e., probe).</p>3<p>P-threshold of 8.4×10⁻⁹ corresponds to the significance threshold used in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004818#pgen-1004818-t001" target="_blank">Table 1</a> (FDR of 0.05). At this threshold, the 189 signals with a <i>cis</i>-probe and the 245 signals without a <i>cis</i>-probe constitute the 434 eQTL signals (comprised of 414 unique genes reported in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004818#pgen-1004818-t001" target="_blank">Table 1</a>).</p>4<p>Mediated is defined as <i>trans</i>-eQTL signals with a “mediation proportion” estimate>0 and Sobel P<10⁻⁵.</p><p>Percent of <i>trans</i>-eQTL signals^{<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004818#nt105" target="_blank">1</a>} showing evidence of <i>cis</i>-mediation according to LD between the lead <i>trans</i>-eSNP and the lead <i>cis</i>-eSNP and the P-threshold for <i>trans</i>-eQTL analysis.</p

The presence of unmeasured confounding of the “<i>cis</i>-mediator”-“<i>trans</i>-gene” relationship can bias mediation estimates.

<p>We use simulated data to demonstrate that an unobserved variable U which affects both the <i>cis</i>-mediator by (effect size of β_U-<i>cis</i>) and the <i>trans-</i>gene (effect size of β_U-trams  =  |β_U-<i>cis</i>|) can bias the estimate of the “direct effect” of the SNP on the <i>trans</i>-gene (β_adj), resulting in bias in the estimate of the proportion of the <i>trans</i>-eQTL effect that is mediated (β - β_adj)/β). All simulated scenarios are “complete mediation”, so the true value of “proportion mediated” is 1.0 (horizontal line). Mediation scenarios are categories according to the strength of the <i>cis</i>-eQTL, in terms of r², and the strength of the effect of the <i>cis</i>-gene on the <i>trans</i>-gene (β<i>_cis</i>_{-<i>trans</i>}). The SNP is coded as the number of alleles which increase the abundance of the <i>cis</i>-transcript.</p

FCN1 expression is the primary mediator of the <i>trans</i>-eQTL at the 9q34.3 white blood cell subtype locus, affecting expression of four genes in <i>trans</i>.

<p>The P-values (left) and beta coefficients (right) for four <i>trans</i>-eQTL associations in the FCN1 region are reduced in significance after adjusting for FCN1 expression.</p

Theoretical framework for <i>cis</i>-mediation of <i>trans</i>-eQTLs.

<p>Panel (A) shows a causal diagram, in which a causal variant (SNP_causal) affects expression of a <i>cis</i>-transcript (gene<i>_cis</i>) which in turn affects expression of a distant gene (gene<i>_trans</i>). When SNP_causal is measured and is the strongest associated SNP (i.e., “lead SNP”) for both the <i>trans</i>- and <i>cis</i>-eQTL association signals, no other SNPs are involved in mediation analysis. Panel (B) shows the causal diagram underlying an eQTL mediation analysis when the causal variant is unmeasured or is not the lead SNP for both the <i>trans</i>- and <i>cis</i>-eQTL association signals. Thus, the lead SNP for gene<i>_cis</i> and gene<i>_trans</i> may be different, and are noted here as SNP_{lead-<i>cis</i>} and SNP_{lead-<i>trans</i>}, respectively. Solid lines represent causal effects, and dotted lines represent non-causal correlation, including linkage disequilibrium (LD).</p

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies