Molecular genetic overlap in bipolar disorder, schizophrenia, and major depressive disorder

Abstract

Objectives: Genome-wide association studies (GWAS) in complex phenotypes, including psychiatric disorders, have yielded many replicated findings, yet individual markers account for only a small fraction of the inherited differences in risk. We tested the performance of polygenic models in discriminating between cases and healthy controls and among cases with distinct psychiatric diagnoses.

Methods: GWAS results in bipolar disorder (BD), major depressive disorder (MDD), schizophrenia (SZ), and Parkinson's disease (PD) were used to assign weights to individual alleles, based on odds ratios. These weights were used to calculate allele scores for individual cases and controls in independent samples, summing across many single nucleotide polymorphisms (SNPs). How well allele scores discriminated between cases and controls and between cases with different disorders was tested by logistic regression.

Results: Large sets of SNPs were needed to achieve even modest discrimination between cases and controls. The most informative SNPs were overlapping in BD, SZ, and MDD, with correlated effect sizes. Little or no overlap was seen between allele scores for psychiatric disorders and those for PD.

Conclusions: BD, SZ, and MDD all share a similar polygenic component, but the polygenic models tested lack discriminative accuracy and are unlikely to be useful for clinical diagnosis.

Figure 1

Whole-genome prediction: Areas under the curve (AUC) for various prediction pairings (psychiatric disorders, a. to d., and between psychiatric disorders and Parkinson disease [PD], e. to g.)

Figure 1

Whole-genome prediction: Areas under the curve (AUC) for various prediction pairings (psychiatric disorders, a. to d., and between psychiatric disorders and Parkinson disease [PD], e. to g.)

Figure 2. Relationship between case status and allele score (in German sample), when SNPs consistently associated with bipolar disorder at p<0.05 in two other samples (GAIN and WTCCC) are used

The allele score as obtained through the --score function in PLINK was divided into quartiles (x-axis) and plotted against the ratio of cases to controls (relative frequency) in each quartile range. An exponential line (gray) gives a good fit to the data (r²=0.98; lowess goodness of fit). To give an example for the sensitivity and specificity of BD, at a threshold allele score of 0.003 (97th percentile) the test has 47% specificity and 70% sensitivity.