Evaluating historical candidate genes for schizophrenia

Abstract

Prior to the genome-wide association era, candidate gene studies were a major approach in schizophrenia genetics. In this invited review, we consider the current status of 25 historical candidate genes for schizophrenia (for example, COMT, DISC1, DTNBP1 and NRG1). The initial study for 24 of these genes explicitly evaluated common variant hypotheses about schizophrenia. Our evaluation included a meta-analysis of the candidate gene literature, incorporation of the results of the largest genomic study yet published for schizophrenia, ratings from informed researchers who have published on these genes, and ratings from 24 schizophrenia geneticists. On the basis of current empirical evidence and mostly consensual assessments of informed opinion, it appears that the historical candidate gene literature did not yield clear insights into the genetic basis of schizophrenia. A likely reason why historical candidate gene studies did not achieve their primary aims is inadequate statistical power. However, the considerable efforts embodied in these early studies unquestionably set the stage for current successes in genomic approaches to schizophrenia.

Figure 1

Candidate gene publications per gene and per year. For each gene, the number of publications is indicated on the Y-axis, and the year is the X-axis. The data shown are from a PubMed query: (gene [All Fields] OR “protein name”[All Fields]) AND (“schizophrenia”[MeSH Terms] OR “schizophrenia”[All Fields]). The goal of this PubMed query was to provide a rough gauge of the impact of a candidate gene on the field (which differs from the “pre-GWAS” column in Table 1).

Figure 2. How many biologically interesting human genes are there?

This bioinformatic analysis addressed the question: how many human genes are of legitimate interest to an integrative neuroscientist or psychiatric geneticist? (A) We intersected 19,304 gene models from GENCODE (v17, “KNOWN” or “protein_coding”) with multiple data sources. Some genes can be in multiple categories. (B) Summary statistics (1=in set, 0=not in set): 35.6% of all genes are in classes A or B (=6869/19304), and 61.4% of all genes are in classes A, B, or C (=11849/19304). These numbers are conservative as adding “expression in brain at any developmental stage” would increase the numbers further. Thus, sizable proportions of all genes are of potential interest to a biologist. Biological interest is an imprecise criterion for the salience of a finding.