Informative phenotypes for genetic studies of psychiatric disorders

Abstract

Despite its initial promise, there has been both progress and some set backs in genetic studies of the major psychiatric disorders of childhood and adulthood. Finding true susceptibility genes may be delayed because the most genetically informative phenotypes are not being used on a regular basis in linkage analysis and association studies. It is highly likely that using alternative phenotypes instead of DSM diagnostic categories will lead more rapid success in the search for these susceptibility genes. The objective of this paper is to describe the different types of informative phenotypes that can be employed in psychiatric genetic studies, to clarify their uses, to identify several methodologic issues the design and conduct of linkage and association studies that use alternative phenotypes and finally to suggest possible solutions to those difficulties. This is a conceptual review with a focus on methodological issues that may arise in psychiatric genetics and examples are taken from the literature on autism, schizophrenia, bipolar disorder, and alcoholism.

Chromosome 13q13–q14 locus overlaps mood and psychotic disorders: the relevance for redefining phenotype

“…42,43 In that respect, in five SZ kindreds of Celtic origin that were affected with language impairment or dyslexia, Bartlett et al 44 observed a parametric multipoint lod score of 3.92 with that cognitive impairment in a region of 13q that may overlap the present findings. As neurocognitive impairments have been shown to be shared by patients with SZ or BP, 45 and their unaffected relatives, 46,47 cognitive intermediate phenotypes might help to investigate further the mechanisms involved in chromosome 13q.…”

“…As neurocognitive impairments have been shown to be shared by patients with SZ or BP, 45 and their unaffected relatives, 46,47 cognitive intermediate phenotypes might help to investigate further the mechanisms involved in chromosome 13q. 42 Also, the concurrent investigation of SZ and BP within the same study may bring advantages to modeling the disease, having in mind the probable joint implications of several susceptibility genes and of epigenetic effects involving environmental factors the nature and timing of which may contribute to explain commonalities as well as specificities in mechanisms underlying psychiatric disorders. 10,48 …”

Symptom dimensions as alternative phenotypes to address genetic heterogeneity in schizophrenia and bipolar disorder

“…In the past few years, significant efforts have been invested in bridging the gap between susceptible genotypes and diagnostic criteria by searching for alternative phenotypes, representing an aspect of the disorder believed to be influenced by fewer genes. 1 Given the well-known clinical heterogeneity of several psychiatric disorders, an informative phenotype may also result from the use of such alternative phenotypes to identify subgroups in which the relationship between genotype and diagnosis is more direct, simpler and stronger than on the total sample. The hypothesis that underlies such an approach is that genetic heterogeneity accounts largely for the variation seen in clinical expression.…”

Immune Dysfunction in Autism Spectrum Disorder

“…Modern microarray based technology allows for the genotyping of thousands of genetic polymorphisms on a single chip, however, other issues such as case/control selection and statistical evaluation are especially important when examining large amounts of subjects and polymorphisms. Several large studies examining hundreds of thousands of single nucleotide polymorphisms (SNPs) have been exhaustively tested in thousands of cases and thousands of controls in an effort to find disease associations (Szatmari et al, 2007;Veenstra-VanderWeele et al, 2004). Three genome-wide association studies (GWAS) each with over 1,000 subjects did not replicate each other's findings for candidate genes (Anney et al, 2010;Wang et al, 2009;Weiss et al, 2009).…”

“…There is increasing interest in using phenotypic subgroups of psychiatric disorders in the detection of susceptibility genes (Tsuang, 2001). Szatmari et al (2007) discusses ways to increase sample size and identify genetically informative phenotypes which will segregate with susceptibility loci and ultimately lead to a causative gene. Recent advances in genetic analysis methods are positively impacting autism research.…”