Risk and information evaluation of prioritized genes for complex traits: Application to bipolar disorder

Abstract

Many susceptibility genes for complex traits were identified without conclusive findings. There is a strong need to integrate rapidly accumulated genomic data from multi-dimensional platforms, and to conduct risk evaluation for potential therapeutic and diagnostic usages. We set up an algorithm to computationally search for optimal weight-vector for various data sources, while minimized potential noises. Through gene-prioritization framework, combined scores for the resulting prioritized gene-set were calculated using a genome-wide association (GWA) dataset, following with evaluation using weighted genetic risk score and risk-attributed information using an independent GWA dataset. The significance of association of GWA data was corrected for gene length. Enriched functional pathways were identified for the prioritized gene-set using the Gene Ontology analysis. We illustrated our framework with bipolar disorder. 233 prioritized genes were identified from 10,830 candidates that curated from six platforms. The prioritized genes were significantly enriched (P(adjusted) < 1 × 10(-5)) in 18 biological functions and molecular mechanisms including membrane, synaptic transmission, transmission of nerve impulse, integral to membrane, and plasma membrane. Our risk evaluation demonstrated higher weighted genetic risk score in bipolar patients than controls (P-values ranged from 0.002 to 3.8 × 10(-6)). Substantial risk-information (71%) was extracted from prioritized genes for bipolar illness than other candidate-gene sets. Our evidence-based prioritized gene-set provides opportunity to explore the complex network and to conduct follow-up basic and clinical studies for complex traits.

Identification of Susceptible Loci and Enriched Pathways for Bipolar II Disorder Using Genome-Wide Association Studies

“…Compared with genetic findings in previous GWA studies of BP or BP-I (The Wellcome Trust Case Control Consortium, 2007; Baum et al, 2008; Ferreira et al, 2008; Lee et al, 2011; Kuo et al, 2014; Muhleisen et al, 2014), there are no overlapping genes reported in this GWA study of BP-II. Previous susceptibility loci included ANK3 , ODZ4 , DGKH , SP8 , ST8SIA2 , KCTD12 , CACNB2 , KCNH7 , MYST4 , NRXN3 , SEMA3D , PALB2 , ITIH3 , CACNA1C , among others.…”

“…The identified pathway of the neurological system process is also an important one. Previously, we reported 233 prioritized candidate-genes for BP (namely BPDgenes) from multi-dimensional data sources (Kao et al, 2014). There are 17 overlapping genes ( CLRN1 , DRD4 , GCH1 , GRIA1 , GRIK1 , GRIN2B , GRM1 , HTR3B , HTR6 , KCNMA1 , KCNQ3 , KLK8 , NOVA1 , SLC6A4 , SYN3 , and TGFB2 ) between the BPDgenes and genes in this pathway.…”

“…Recently, we proposed a GRS method (Kao et al, 2014) and successfully applied it to evaluate the risk information in a prioritized candidate-gene set of BP. Markers in weak LD ( r 2 <0.2) with each other were selected to calculate GRS.…”

“…In particular, large scale genome-wide association (GWA) studies are commonly employed in the last decade to search susceptibility loci for complex human traits (McCarthy et al, 2008). Several GWA studies have identified many loci for the risk of developing BP (The Wellcome Trust Case Control Consortium, 2007; Baum et al, 2008; Ferreira et al, 2008; Sklar et al, 2008; Lee et al, 2011; Kuo et al, 2014; Muhleisen et al, 2014; Xu et al, 2014); however, conclusive and replicated findings are relatively scattered. Some examples are the ANK3 and CACNA1C genes (Ferreira et al, 2008; Muhleisen et al, 2014).…”

“…To identify disease-associated genetic variants, one of the crucial steps is to define phenotypically homogeneous patient groups. However, patients in previous GWA studies of BP are usually a mixture of the BP-I and BP-II subgroups, with a few focused on only the BP-I subtype (Baum et al, 2008; Sklar et al, 2008; Lee et al, 2011; Kuo et al, 2014) but none solely on the BP-II subtype. The BP-II subtype is relatively understudied in many regards.…”