The Consortium on the Genetics of Schizophrenia: neurocognitive endophenotypes

Abstract

The Consortium on the Genetics of Schizophrenia (COGS) is a 7-site collaboration that examines the genetic architecture of quantitative endophenotypes in families with schizophrenia. Here we review the background and rationale for selecting neurocognitive tasks as endophenotypic measures in genetic studies. Criteria are outlined for the potential of measures as endophenotypic vulnerability markers. These include association with illness, state independence (ie, adequate test-retest stability, adequate between-site reliability, impairments in patients not due to medications, impairments observed regardless of illness state), heritability, findings of higher rates in relatives of probands than in the general population, and cosegregation within families. The COGS required that, in addition, the measures be "neurocognitive" and thus linked to neurobiology and that they be feasible in multisite studies. The COGS neurocognitive assessment includes measures of attention, verbal memory, working memory, and a computerized neurocognitive battery that also includes facial processing tasks. Here we describe data demonstrating that these neurobehavioral measures meet criteria for endophenotypic candidacy. We conclude that quantitative neurocognitive endophenotypes need further evidence for efficacy in identifying genetic effects but have the potential of providing unprecedented insight into gene-environment interaction related to dimensions of brain and behavior in health and disease.

Fig. 1

Examples of the stimuli in the computerized Degraded Stimulus Continuous Performance Test. The “0” is the target stimulus. Printed with permission of Keith H. Nuechterlein.

Fig. 2

The Letter-Number Sequencing Test comprises 2 conditions. In the Letter-Number Sequencing task (LNS)–forward condition, the tester verbally presents different sets of increasingly longer sequences of intermixed letters and numbers at a rate of 1/second. After each sequence, the participant is asked to repeat the numbers and letters in the same exact order. In the LNS-reordered condition, the tester again verbally presents increasingly longer sequences of intermixed numbers and letters at a rate of 1/second. After each sequence, the participant is asked to repeat the numbers in ascending order first and then the letters in alphabetical order. In both conditions, the letter-number sequences range from 2 stimuli (eg, A–3) up to a maximum length of 8 stimuli. Three trials at each length are presented. Both conditions are discontinued when the subject fails 3 consecutive trials of the same length. Within each condition, one point is scored for each correctly repeated sequence (maximum total score for each condition is 21 points). Sample items from the Letter-Number Sequencing Test.

Fig. 3

Examples of stimuli from the Penn computerized neurocognitive battery.