Suggestive linkage of the child behavior checklist juvenile bipolar disorder phenotype to 1p21, 6p21, and 8q21.
OBJECTIVE
Several studies have documented a profile of elevated scores on the Attention Problems, Aggressive Behavior and Anxious/Depressed scales of the Child Behavior Checklist (CBCL) in youth with bipolar disorder. The sum of these scales, referred to as the CBCL Juvenile Bipolar Disorder (JBD) phenotype, has modest diagnostic utility, and high scores are associated with severity of psychopathology and poor outcome. Recently, a genomewide linkage scan of this measure in ADHD sibling pairs revealed a region of suggestive linkage on chromosome 2q21. The current study aimed to further identify quantitative trait loci that influence the CBCL-JBD phenotype by using a dense and thus, arguably, more powerful set of single-nucleotide polymorphism markers in a different ADHD sibling pair sample.


METHODS
Subjects were 765 individuals from 154 families with CBCL data enrolled in a linkage study of ADHD. Linkage analyses were completed using a multipoint maximum likelihood variance components approach implemented using the statistical program SOLAR.


RESULTS
Heritability of the CBCL-JBD phenotype was estimated at .71. Although no regions of the genome surpassed empirically derived criteria for significant linkage (p = .000038), peaks on 1p21.1 (p = .00037; LOD = 2.76), 6p21.3 (p = .00054; LOD =2.60), and 8q21.13 (p = .00081; LOD = 2.44) surpassed the threshold for suggestive linkage (p = .002). These regions have been highlighted in genomewide scans of bipolar disorder in adults, schizophrenia, autism, and ADHD.


CONCLUSIONS
Findings raise the possibility that genes in these regions influence variation on the CBCL-JBD scale and the emotional and behavioral dysregulation associated with severe psychopathology.
Doyle
Alysa E
AE
Psychiatric and Neurodevelopmental Genetics Unit, Harvard Medical School, Center for Human Genetics Research at Massachusetts General Hospital, Boston MA 02114, USA. aedoyle@partners.org
Biederman
Joseph
J
Ferreira
Manuel A R
MA
Wong
Patricia
P
Smoller
Jordan W
JW
Faraone
Stephen V
SV
D000293:Adolescent; D000374:Aggression; D001007:Anxiety; D001288:Attention; D001289:Attention Deficit Disorder with Hyperactivity / Q000235:genetics; D001321:Autistic Disorder / Q000235:genetics; D001714:Bipolar Disorder / Q000235:genetics / Q000523:psychology; D057189:Checklist; D002648:Child; D002652:Child Behavior / Q000502:physiology / Q000523:psychology; D002653:Child Behavior Disorders / Q000235:genetics; D002878:Chromosomes, Human, Pair 1; D002896:Chromosomes, Human, Pair 6; D002898:Chromosomes, Human, Pair 8; D003863:Depression; D005819:Genetic Markers; D055106:Genome-Wide Association Study; D006801:Humans; D011569:Psychiatric Status Rating Scales; D040641:Quantitative Trait Loci; D012559:Schizophrenia / Q000235:genetics
D005819:Genetic Markers
Biol Psychiatry. 2009 Jun 15;65(12):1055-62
19251251
Biol Psychiatry. 2006 Nov 1;60(9):903-11
16650832
Trends Neurosci. 2009 Feb;32(2):69-72
19135727
Am J Hum Genet. 1999 Aug;65(2):493-507
10417292
Am J Hum Genet. 2008 Feb;82(2):477-88
18252227
Arch Gen Psychiatry. 1982 Aug;39(8):879-83
7103676
Child Dev. 1985 Feb;56(1):265-75
3987406
J Affect Disord. 1998 Nov;51(2):93-100
10743842
Dialogues Clin Neurosci. 2008;10(2):215-28
18689291
Harv Rev Psychiatry. 1995 Nov-Dec;3(4):227-30
9384951
J Clin Psychiatry. 2009 Apr 21;70(5):732-40
19389330
Am J Psychiatry. 1994 Jul;151(7):1048-54
8010363
Am J Hum Genet. 2005 Dec;77(6):937-44
16380906
Biol Psychiatry. 2005 Oct 1;58(7):562-8
16239161
J Child Psychol Psychiatry. 2009 Mar;50(3):203-15
19309325
J Am Acad Child Adolesc Psychiatry. 2007 Jan;46(1):107-125
17195735
Bipolar Disord. 2007 Dec;9(8):895-900
18076540
Am J Hum Genet. 2003 Jul;73(1):34-48
12802786
Mol Psychiatry. 2009 Mar;14(3):252-60
19065143
Am J Hum Genet. 1998 May;62(5):1198-211
9545414
J Affect Disord. 2009 Mar;113(3):227-35
18632161
Science. 2000 Apr 28;288(5466):678-82
10784452
Am J Hum Genet. 1995 May;56(5):1212-23
7726179
Mol Psychiatry. 2000 Nov;5(6):638-49
11126394
Mol Psychiatry. 2008 Jun;13(6):570-84
18347602
J Am Acad Child Adolesc Psychiatry. 2003 Dec;42(12):1494-503
14627885
Biol Psychiatry. 2003 Jun 1;53(11):1021-7
12788247
Child Psychiatry Hum Dev. 2007 Jun;38(1):47-55
17160586
Child Psychiatry Hum Dev. 1995 Fall;26(1):11-8
7587476
J Am Acad Child Adolesc Psychiatry. 1995 Jul;34(7):867-76
7649957
Bipolar Disord. 2005 Dec;7(6):525-35
16403178
Mol Psychiatry. 2008 Jun;13(6):558-69
18317468
J Am Acad Child Adolesc Psychiatry. 2001 Sep;40(9):1094-102
11556634
Biol Psychiatry. 2007 Jul 15;62(2):115-20
16950211
Dev Psychopathol. 2004 Spring;16(2):461-76
15487606
Am J Psychiatry. 1995 Feb;152(2):271-3
7840364
J Am Acad Child Adolesc Psychiatry. 1995 Jul;34(7):946-54; discussion 954-6
7649966
Biol Psychiatry. 2006 Nov 1;60(9):912-20
16735031
J Am Acad Child Adolesc Psychiatry. 2008 Oct;47(10):1151-7
18724256
J Child Psychol Psychiatry. 2009 Oct;50(10):1291-300
19486226
Am J Hum Genet. 2007 Nov;81(5):974-86
17924339
J Mol Neurosci. 2007;31(3):221-43
17726228
Biol Psychiatry. 2005 Oct 1;58(7):569-75
15950197
Nature. 2007 Jun 7;447(7145):661-78
17554300
Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1399-411
18973233
Bipolar Disord. 2005 Dec;7(6):518-24
16403177
J Affect Disord. 1998 Nov;51(2):113-21
10743844
Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1387-91
18081027
Proc Natl Acad Sci U S A. 2007 Jul 10;104(28):11694-9
17609372
Curr Psychiatry Rep. 2002 Apr;4(2):146-52
11914177
Child Adolesc Psychiatr Clin N Am. 2009 Apr;18(2):441-53, x
19264272
Am J Psychiatry. 2008 Sep;165(9):1163-71
18519524
J Child Adolesc Psychopharmacol. 2003 Winter;13(4):471-88
14977460
J Paediatr Child Health. 1999 Apr;35(2):199-203
10365361
J Child Adolesc Psychopharmacol. 2009 Feb;19(1):23-30
19232020
J Psychiatr Res. 2002 Sep-Oct;36(5):337-45
12127602
Am J Med Genet B Neuropsychiatr Genet. 2008 Dec 5;147B(8):1337-44
18980221