Although schizophrenia has a high heritability, the...
Although schizophrenia has a high heritability, the genetic effects conferring risk to schizophrenia are complex and comprise multifactorial polygenic inheritance. “Endophenotypes” are often synonymous with cognitive and brain deviations, are hypothetically narrower constructs of genetic risk, and are assumed to be closer to the gene effects in the disease pathway than the clinical phenotypes. Lien and colleagues used this familiar strategy of endophenotypes (Toulopoulou et al., 2007; Owens et al., 2010) to perform a series of genomewide QTL linkage scans in a large sample of Han Chinese families with schizophrenia. QTL genomewide scans identified 12q24.32 as a novel linkage region for conferring susceptibility to a single index of sustained attention deficit (undegraded CPT hit rate) in patients with schizophrenia. The highest linkage signal identified in this study (NPL-Z scores of 3.32 on 12q24.32) was greater than that in their original linkage study using a dichotomous disease phenotype (NPL-Z scores of 2.88 on 10q22.3) (Faraone et al., 2006), suggesting that the endophenotypic approach might be more sensitive. Though, as the authors correctly point out, the locus identified is different from the original study, which could suggest that the locus is relevant to variation in cognitive performance rather than schizophrenia. The main question in my mind is whether it is appropriate to treat single indexes within tests as if they were stable and independent phenomena, neither of which is true. It seems to me that if, for example, the authors carried out a factor analysis and then derived the relevant factors, it would be much more meaningful and therefore potentially more likely to be replicated.
Toulopoulou T, Picchioni M, Rijsdijk F, Hua-Hall M, Ettinger U, Sham P, Murray R. Substantial genetic overlap between neurocognition and schizophrenia: genetic modeling in twin samples (2007). Arch Gen Psychiatry. 64(12):1348-55. Abstract
Owens SF, Rodger AK., Picchioni MM., Rijsdijk FV., Stahl D, Vassos E, Collier DA, Murray, RM, Toulopoulou T. (2010) Genetic overlap between episodic memory deficits and schizophrenia – results from The Maudsley Twin Study. Psychol Med. May 12:1-12. Abstract
Faraone SV, Hwu HG, Liu CM, Chen WJ, Tsuang MM, Liu SK, Shieh MH, Hwang TJ, Ou-Yang WC, Chen CY, Chen CC, Lin JJ, Chou FH, Chueh CM, Liu WM, Hall MH, Su J, Van Eerdewegh P, Tsuang MT. Genome scan of Han Chinese schizophrenia families from Taiwan: confirmation of linkage to 10q22.3. Am J Psychiatry . 2006 Oct 1 ; 163(10):1760-6. Abstract
It was an interesting approach by Lien et al. to perform a...
It was an interesting approach by Lien et al. to perform a linkage study on neurocognitive performance in schizophrenia families, and they describe a valuable cohort. Unfortunately, as the authors acknowledge, given the margin of significance (p = 0.03) and the number of tests performed, it is difficult to see this is anything other than a false positive (only the different genetic markers were corrected for, not the multiple phenotypes). False positives have plagued the world of schizophrenia genetics, and it doesn’t seem unreasonable to require that linkage (and association) results are confirmed in a replication cohort before they are published.