Elsevier

Biological Psychiatry

Volume 64, Issue 12, 15 December 2008, Pages 1051-1059
Biological Psychiatry

Archival Report
Abnormal Auditory N100 Amplitude: A Heritable Endophenotype in First-Degree Relatives of Schizophrenia Probands

https://doi.org/10.1016/j.biopsych.2008.06.018Get rights and content

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.

Section snippets

Subject Ascertainment

Adults with and without schizophrenia were recruited through flyers and print and electronic media. Schizophrenia subjects were also ascertained by mental health providers and local chapters of the National Alliance on Mental Illness. Pedigrees were ascertained through the identified probands who met DSM-IV criteria for schizophrenia. The minimum requirement for pedigree ascertainment in COGS was a schizophrenia proband, two parents and one sibling unaffected with schizophrenia to provide DNA

Heritability

Heritability estimates are presented in Table 3. All dependent measures exhibited statistically significant heritability, with S1 being the most and S2/S1 the least heritable. Age and gender were significant covariates for S1, but not S2.

Bivariate Correlations

Table 4 presents the bivariate Pearson correlations for the three dependent measures for the total sample and separately within each diagnostic group. There was a moderate association between S1 and S2, which was comparable across the three groups. Stimulus

Discussion

These findings support two basic conclusions: 1) N100 amplitude is a robust heritable trait; and 2) reduced N100 amplitude, which has been observed repeatedly in schizophrenia patients, is also present in a subset of unaffected first-degree relatives. This simple measure of auditory sensory processing therefore appears to meet two essential criteria of a viable endophenotype for genetic studies. A similar conclusion cannot be drawn for N100 gating. Although the gating measure was heritable, it

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