title: Paternal age of schizophrenia probands and endophenotypic differences from unaffected siblings.
abstract: We evaluated the discrepancy of endophenotypic performance between probands with schizophrenia and unaffected siblings by paternal age at proband birth, a possible marker for de novo mutations. Pairs of schizophrenia probands and unaffected siblings (N=220 pairs) were evaluated on 11 neuropsychological or neurophysiological endophenotypes previously identified as heritable. For each endophenotype, the sibling-minus-proband differences were transformed to standardized scores. Then for each pair, the average discrepancy was calculated from its standardized scores. We tested the hypothesis that the discrepancy is associated with paternal age, controlling for the number of endophenotypes shared between proband and his or her sibling, and proband age, which were both associated with paternal age. The non-significant association between the discrepancy and paternal age was in the opposite direction from the hypothesis. Of the 11 endophenotypes only sensori-motor dexterity was significant, but in the opposite direction. Eight other endophenotypes were also in the opposite direction, but not significant. The results did not support the hypothesized association of increased differences between sibling/proband pairs with greater paternal age. A possible explanation is that the identification of heritable endophenotypes was based on samples for which schizophrenia was attributable to inherited rather than de novo/non-inherited causes.
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai School, One Gustave L. Levy Place, Box 1230, New York, NY, USA.
authors.forename: James
authors.initials: J
authors.lastname: Schmeidler
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Lazzeroni
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA, USA.
authors.forename: Neal R
authors.initials: NR
authors.lastname: Swerdlow
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai School, One Gustave L. Levy Place, Box 1230, New York, NY, USA.
authors.forename: Rui P
authors.initials: RP
authors.lastname: Ferreira
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA, USA; VISN-22 Mental Illness Research, Education, and Clinical Center, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Braff
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Monica E
authors.initials: ME
authors.lastname: Calkins
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA, USA.
authors.forename: Kristin S
authors.initials: KS
authors.lastname: Cadenhead
authors.affiliation: Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Freedman
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at University of California, Los Angeles, CA, USA; VA Greater Los Angeles Health Care System, Los Angeles, CA, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Green
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA, USA.
authors.forename: Tiffany A
authors.initials: TA
authors.lastname: Greenwood
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Raquel E
authors.initials: RE
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Ruben C
authors.initials: RC
authors.lastname: Gur
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA, USA; VISN-22 Mental Illness Research, Education, and Clinical Center, VA San Diego Healthcare System, San Diego, CA, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Light
authors.affiliation: Department of Psychiatry, University of Colorado Health Sciences Center, Denver, CO, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Olincy
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at University of California, Los Angeles, CA, USA.
authors.forename: Keith H
authors.initials: KH
authors.lastname: Nuechterlein
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.
authors.forename: Allen D
authors.initials: AD
authors.lastname: Radant
authors.affiliation: Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Harvard Medical School Department of Psychiatry, Boston, MA, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Seidman
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai School, One Gustave L. Levy Place, Box 1230, New York, NY, USA; VISN-3 Mental Illness Research, Education, and Clinical Center, James J. Peters VA Medical Center, New York, NY, USA.
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Siever
authors.affiliation: Massachusetts Mental Health Center Public Psychiatry Division of the Beth Israel Deaconess Medical Center, Harvard Medical School Department of Psychiatry, Boston, MA, USA.
authors.forename: William S
authors.initials: WS
authors.lastname: Stone
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Sprock
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at University of California, Los Angeles, CA, USA; VA Greater Los Angeles Health Care System, Los Angeles, CA, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Sugar
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA; VISN-20 Geriatric Research, Education, and Clinical Center, VA Puget Sound Health Care System, Seattle, WA, USA.
authors.forename: Debby W
authors.initials: DW
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of California, San Diego, CA, USA.
authors.forename: Ming T
authors.initials: MT
authors.lastname: Tsuang
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Bruce I
authors.initials: BI
authors.lastname: Turetsky
authors.affiliation: Department of Psychiatry, Icahn School of Medicine at Mount Sinai School, One Gustave L. Levy Place, Box 1230, New York, NY, USA; James J. Peters Veterans Affairs Medical Center, Bronx, NY 10468, USA. Electronic address: jeremy.silverman@mssm.edu.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
mesh_terms: D000328:Adult; D058068:Endophenotypes / Q000032:analysis*; D005260:Female; D006801:Humans; D008297:Male; D009154:Mutation; D010331:Paternal Age; D012559:Schizophrenia / Q000235:genetics*; D035781:Siblings
keywords: Copy number variants; De novo mutations; Familial schizophrenia; Genetic risk; Sporadic schizophrenia