Sex-specific association of the Reelin gene with bipolar disorder.
The Reelin gene (RELN) encodes a secretory glycoprotein critical for brain development and synaptic plasticity. Post-mortem studies have shown lower Reelin protein levels in the brains of patients with schizophrenia and bipolar disorder (BP) compared with controls. In a recent genome-wide association study of schizophrenia, the strongest association was found in a marker within RELN, although this association was seen only in women. In this study, we investigated whether genetic variation in RELN is associated with BP in a large family sample. We genotyped 75 tagSNPs and 6 coding SNPs in 1,188 individuals from 318 nuclear families, including 554 affected offspring. Quality control measures, transmission-disequilibrium tests (TDTs), and empirical simulations were performed in PLINK. We found a significant overtransmission of the C allele of rs362719 to BP offspring (OR = 1.47, P = 5.9 x 10(-4)); this withstood empirical correction for testing of multiple markers (empirical P = 0.048). In a hypothesis-driven secondary analysis, we found that the association with rs362719 was almost entirely accounted for by overtransmission of the putative risk allele to affected females (OR(Female) = 1.79, P = 8.9 x 10(-5) vs. OR(Male) = 1.12, P = 0.63). These results provide preliminary evidence that genetic variation in RELN is associated with susceptibility to BP and, in particular, to BP in females. However, our findings should be interpreted with caution until further replication and functional assays provide convergent support.
Goes
F S
FS
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
Willour
V L
VL
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
Zandi
P P
PP
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.|Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Belmonte
P L
PL
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
MacKinnon
D F
DF
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
Mondimore
F M
FM
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
Schweizer
B
B
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
DePaulo
J R
JR
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
Gershon
E S
ES
Department of Psychiatry, University of Chicago, Chicago, Illinois.
McMahon
F J
FJ
Genetic Basis of Mood and Anxiety Disorders Unit, Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland.
Potash
J B
JB
Department of Psychiatry, Johns Hopkins School of Medicine, Baltimore, Maryland.
D000483:Alleles; D001714:Bipolar Disorder / Q000235:genetics*; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005192:Family Health; D005260:Female; D005819:Genetic Markers; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D011786:Quality Control; D000091042:Reelin Protein; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics; D012697:Serine Endopeptidases / Q000235:genetics*; D012737:Sex Factors
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D005819:Genetic Markers; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; C000717127:RELN protein, human; D012697:Serine Endopeptidases
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