title: Neuropsychological and dimensional behavioral trait profiles in Costa Rican ADHD sib pairs: Potential intermediate phenotypes for genetic studies.
abstract: Attention deficit hyperactivity disorder (ADHD) is associated with substantial functional impairment in children and in adults. Many individuals with ADHD have clear neurocognitive deficits, including problems with visual attention, processing speed, and set shifting. ADHD is etiologically complex, and although genetic factors play a role in its development, much of the genetic contribution to ADHD remains unidentified. We conducted clinical and neuropsychological assessments of 294 individuals (269 with ADHD) from 163 families (48 multigenerational families created using genealogical reconstruction, 78 affected sib pair families, and 37 trios) from the Central Valley of Costa Rica (CVCR). We used principal components analysis (PCA) to group neurocognitive and behavioral variables using the subscales of the Child Behavior Checklist (CBCL) and 15 neuropsychological measures, and created quantitative traits for heritability analyses. We identified seven cognitive and two behavioral domains. Individuals with ADHD were significantly more impaired than their unaffected siblings on most behavioral and cognitive domains. The verbal IQ domain had the highest heritability (92%), followed by auditory attention (87%), visual processing speed and problem solving (85%), and externalizing symptoms (81%). The quantitative traits identified here have high heritabilities, similar to the reported heritability of ADHD (70-90%), and may represent appropriate alternative phenotypes for genetic studies. The use of multigenerational families from a genetically isolated population may facilitate the identification of ADHD risk genes in the face of phenotypic and genetic heterogeneity.
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California.
authors.forename: Viviana A
authors.initials: VA
authors.lastname: Peskin
authors.affiliation: Child Psychiatry Branch, National Institute of Mental Health, Bethesda, Maryland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ordóñez
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California.
authors.forename: R Scott
authors.initials: RS
authors.lastname: Mackin
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California.
authors.forename: Kevin
authors.initials: K
authors.lastname: Delucchi
authors.affiliation: Department of Psychiatry, Hospital CIMA, San José, Costa Rica.
authors.forename: Silvia
authors.initials: S
authors.lastname: Monge
authors.affiliation: Department of Psychiatry, University of California, Los Angeles, Los Angeles, California.
authors.forename: James J
authors.initials: JJ
authors.lastname: McGough
authors.affiliation: Department of Psychology, University of California, Los Angeles, Los Angeles, California.
authors.forename: Denise A
authors.initials: DA
authors.lastname: Chavira
authors.affiliation: Department of Psychiatry, Hospital CIMA, San José, Costa Rica.
authors.forename: Monica
authors.initials: M
authors.lastname: Berrocal
authors.affiliation: Department of Psychiatry, University of California, San Francisco, San Francisco, California.
authors.forename: Erika
authors.initials: E
authors.lastname: Cheung
authors.affiliation: Department of Psychiatry, Hospital CIMA, San José, Costa Rica.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fournier
authors.affiliation: Departments of Psychiatry and Human Genetics, University of Chicago, Chicago, Illinois.
authors.forename: Judith A
authors.initials: JA
authors.lastname: Badner
authors.affiliation: Department of Psychiatry, Hospital CIMA, San José, Costa Rica.
authors.forename: Luis Diego
authors.initials: LD
authors.lastname: Herrera
authors.affiliation: Department of Psychiatry and Institute for Human Genetics, University of California, San Francisco, San Francisco, California.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Mathews
mesh_terms: D000293:Adolescent; D000328:Adult; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics* / Q000503:physiopathology / Q000523:psychology*; D001519:Behavior; D002648:Child; D003071:Cognition; D003364:Costa Rica; D005163:Factor Analysis, Statistical; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics; D008297:Male; D008957:Models, Genetic; D009483:Neuropsychological Tests; D010375:Pedigree; D010641:Phenotype; D025341:Principal Component Analysis; D035781:Siblings; D055815:Young Adult
keywords: ADHD; cognitive; endophenotypes; heritability; pedigrees
references.citation: J Am Acad Child Adolesc Psychiatry. 2007 Nov;46(11):1437-44
references.pmid: 18049293
references.citation: Child Neuropsychol. 2003 Dec;9(4):237-54
references.pmid: 14972703
references.citation: Am J Med Genet. 2002 Jul 8;114(5):497-508
references.pmid: 12116183
references.citation: Psychiatr Genet. 2004 Mar;14(1):13-23
references.pmid: 15091311
references.citation: Am J Hum Genet. 2004 Dec;75(6):998-1014
references.pmid: 15497111
references.citation: Clin Genet. 2002 Apr;61(4):233-47
references.pmid: 12030885
references.citation: J Am Acad Child Adolesc Psychiatry. 2007 Dec;46(12):1614-21
references.pmid: 18030083
references.citation: J Abnorm Psychol. 2012 May;121(2):360-71
references.pmid: 22428793
references.citation: J Am Acad Child Adolesc Psychiatry. 2008 Jul;47(7):808-16
references.pmid: 18520957
references.citation: Lancet. 2005 Jul 16-22;366(9481):237-48
references.pmid: 16023516
references.citation: Behav Genet. 2012 Jul;42(4):528-38
references.pmid: 22302529
references.citation: J Abnorm Psychol. 2002 May;111(2):279-89
references.pmid: 12003449
references.citation: Proc Natl Acad Sci U S A. 1996 Nov 12;93(23):13060-5
references.pmid: 8917544
references.citation: J Psychiatry Neurosci. 2009 Mar;34(2):88-101
references.pmid: 19270759
references.citation: Am J Med Genet. 2001 Mar 8;105(2):207-13
references.pmid: 11304838
references.citation: J Am Acad Child Adolesc Psychiatry. 2001 Dec;40(12):1410-7
references.pmid: 11765286
references.citation: Schizophr Res. 2011 Sep;131(1-3):52-7
references.pmid: 21745728
references.citation: Neurosci Biobehav Rev. 2003 Nov;27(7):593-604
references.pmid: 14624804
references.citation: J Pediatr Psychol. 2007 Jul;32(6):631-42
references.pmid: 17556405
references.citation: J Am Acad Child Adolesc Psychiatry. 2007 Dec;46(12):1605-13
references.pmid: 18030082
references.citation: Biol Psychiatry. 2005 Jun 1;57(11):1224-30
references.pmid: 15949992
references.citation: Child Neuropsychol. 2011;17(3):209-24
references.pmid: 21287422
references.citation: Psychiatr Genet. 2006 Aug;16(4):159-68
references.pmid: 16829783
references.citation: PLoS One. 2013;8(6):e67002
references.pmid: 23840573
references.citation: Atten Defic Hyperact Disord. 2011 Sep;3(3):291-9
references.pmid: 21779842
references.citation: J Child Psychol Psychiatry. 2005 Jul;46(7):774-803
references.pmid: 15972070
references.citation: J Am Acad Child Adolesc Psychiatry. 2000 Sep;39(9):1135-43
references.pmid: 10986810
references.citation: Genes Brain Behav. 2011 Nov;10(8):844-51
references.pmid: 21815997
references.citation: J Child Psychol Psychiatry. 2006 Nov;47(11):1184-94
references.pmid: 17076758
references.citation: Annu Rev Med. 2002;53:113-31
references.pmid: 11818466
references.citation: Am J Med Genet. 1996 May 31;67(3):244-53
references.pmid: 8725743
references.citation: J Clin Psychiatry. 2006;67 Suppl 8:21-6
references.pmid: 16961426
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):957-63
references.pmid: 18314873
references.citation: Biol Psychiatry. 2005 Jun 1;57(11):1336-46
references.pmid: 15950006
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11485-90
references.pmid: 11572994
references.citation: Pediatrics. 2004 Nov;114(5):e541-7
references.pmid: 15520087
references.citation: Arch Gen Psychiatry. 1982 Aug;39(8):879-83
references.pmid: 7103676
references.citation: Clin Psychol Rev. 2006 Aug;26(4):466-85
references.pmid: 16473440
references.citation: J Abnorm Child Psychol. 1990 Aug;18(4):393-406
references.pmid: 2246431
references.citation: Am J Hum Genet. 2002 Sep;71(3):565-74
references.pmid: 12119601
references.citation: Arch Gen Psychiatry. 2007 Nov;64(11):1242-50
references.pmid: 17984393
references.citation: J Am Acad Child Adolesc Psychiatry. 2007 Dec;46(12):1594-604
references.pmid: 18030081
references.citation: J Abnorm Child Psychol. 2007 Apr;35(2):229-38
references.pmid: 17351752
references.citation: Am J Psychiatry. 2006 Apr;163(4):716-23
references.pmid: 16585449
references.citation: Neuropsychology. 2004 Jul;18(3):543-55
references.pmid: 15291732
references.citation: Psychiatry Clin Neurosci. 2004 Feb;58(1):37-41
references.pmid: 14678455
references.citation: Biol Psychiatry. 2014 Oct 15;76(8):603-15
references.pmid: 24231201
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1399-411
references.pmid: 18973233
references.citation: Am J Hum Genet. 1998 May;62(5):1198-211
references.pmid: 9545414
references.citation: J Am Acad Child Adolesc Psychiatry. 1996 Mar;35(3):343-51
references.pmid: 8714323
references.citation: J Neural Transm (Vienna). 2012 Jan;119(1):95-106
references.pmid: 21626411
references.citation: J Clin Exp Neuropsychol. 2009 Nov;31(8):897-912
references.pmid: 19308775
references.citation: Behav Brain Funct. 2008 Jan 30;4:4
references.pmid: 18234079
references.citation: J Child Psychol Psychiatry. 1995 Nov;36(8):1459-73
references.pmid: 8988278
references.citation: Am J Psychiatry. 1995 Mar;152(3):431-5
references.pmid: 7864271
references.citation: World Psychiatry. 2003 Jun;2(2):104-13
references.pmid: 16946911
references.citation: Behav Genet. 2010 Jul;40(4):505-17
references.pmid: 20361247
references.citation: Mol Psychiatry. 2012 Oct;17(10):960-87
references.pmid: 22105624
references.citation: Br J Psychiatry. 2007 May;190:402-9
references.pmid: 17470954
references.citation: Am J Psychiatry. 2009 Jun;166(6):711-7
references.pmid: 19448185
references.citation: Neurotherapeutics. 2012 Jul;9(3):490-9
references.pmid: 22976615
references.citation: Am J Hum Genet. 2008 Jul;83(1):99-105
references.pmid: 18599010
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2008 Sep 5;147B(6):927-37
references.pmid: 18361436
references.citation: Am J Med Genet B Neuropsychiatr Genet. 2010 Jan 5;153B(1):148-58
references.pmid: 19418498
references.citation: Hum Genet. 2011 Dec;130(6):795-805
references.pmid: 21691774
references.citation: Child Adolesc Psychiatr Clin N Am. 2008 Apr;17(2):261-84, vii-viii
references.pmid: 18295146
references.citation: J Am Acad Child Adolesc Psychiatry. 2004 Dec;43(12):1506-15
references.pmid: 15564820
references.citation: Compr Psychiatry. 2012 May;53(4):379-86
references.pmid: 21696714
references.citation: MMWR Surveill Summ. 2013 May 17;62 Suppl 2:1-35
references.pmid: 23677130
references.citation: J Am Acad Child Adolesc Psychiatry. 2000 Aug;39(8):1064-8
references.pmid: 10939238
references.citation: Am J Psychiatry. 1997 Apr;154(4):532-5
references.pmid: 9090341