Abnormal auditory N100 amplitude: a heritable endophenotype in first-degree relatives of schizophrenia probands

Abstract

Background: N100 evoked potential amplitude and gating abnormalities have been widely observed in schizophrenia patients. However, previous studies have been inconclusive as to whether similar deficits are present in unaffected family members. The Consortium on the Genetics of Schizophrenia (COGS) is a multisite National Institute of Mental Health (NIMH) initiative examining neurocognitive and neurophysiological measures as endophenotypes for genetic studies of schizophrenia. We report initial results from the COGS dataset of auditory N100 amplitude and gating as candidate endophenotypes.

Methods: Evoked potential data were acquired from 142 schizophrenia probands, 373 unaffected first-degree relatives, and 221 community comparison subjects (CCS), using an auditory paired-click stimulation paradigm. Amplitude of the N100 response to each click and the click 2/click 1 ratio were dependent variables. Heritability was estimated based on kinships using Solar v.2.1.2. Group differences were examined after subjects were categorized as either "broad" or "narrow," based on the presence (broad) or absence (narrow) of nonpsychotic psychiatric comorbidity.

Results: Heritability estimates were .40 and .29 for click1 and click2 amplitudes and .22 for the ratio. Broad and narrow patients both had impaired click 1 amplitudes. Broad relatives, but not narrow relatives, exhibited similar impairments. There were no group differences for either click 2 amplitude or the gating ratio.

Conclusions: N100 amplitude is a heritable measure that is abnormal in patients and a subset of relatives for whom psychiatric comorbidity may be a genetically associated phenotype. Auditory N100 gating, although heritable, is less viable as a schizophrenia endophenotype.

Figure 1

Grand average evoked potential waveforms for schizophrenia patients and CCS (top) and unaffected family members and CCS (bottom). Left: "broad" clinical sample with co-morbid psychiatric conditions; Right: "narrow" clinical sample with no co-morbidity. The N100 evoked potential component is the distinct trough at 100 ms (S1) and 600 ms (S2).

Figure 2

Mean (±s.e.) N100 responses for patients, unaffected family members and CCS segregated by "broad" (left) and "narrow" (right) clinical status. Top: Click 1 amplitude (S1); Middle: Click 2 amplitude (S2); Bottom: Gating ratio (S2/S1). Effect size (Cohen's d) and associated significance level is indicated for each patient vs. CCS and family member vs. CCS comparison.

Figure 3

Mean (±s.e.) S1 N100 responses for “broad” unaffected family members and “broad” CCS, segregated into those with substance use disorders (left) and those with other non-psychotic Axis I diagnoses. Effect size (Cohen's d) and associated significance level is indicated for each family member vs. CCS comparison.