Abstract
Bipolar disorder (BPD) is a common psychiatric illness with a complex mode of inheritance. Besides traditional linkage and association studies, which require large sample sizes, analysis of common and rare chromosomal copy number variants (CNVs) in extended families may provide novel insights into the genetic susceptibility of complex disorders. Using the Illumina HumanHap550 BeadChip with over 550,000 SNP markers, we genotyped 46 individuals in a three-generation Old Order Amish pedigree with 19 affected (16 BPD and three major depression) and 27 unaffected subjects. Using the PennCNV algorithm, we identified 50 CNV regions that ranged in size from 12 to 885 kb and encompassed at least 10 single nucleotide polymorphisms (SNPs). Of 19 well characterized CNV regions that were available for combined genotype-expression analysis 11 (58%) were associated with expression changes of genes within, partially within or near these CNV regions in fibroblasts or lymphoblastoid cell lines at a nominal P value <0.05. To further investigate the mode of inheritance of CNVs in the large pedigree, we analyzed a set of four CNVs, located at 6q27, 9q21.11, 12p13.31 and 15q11, all of which were enriched in subjects with affective disorders. We additionally show that these variants affect the expression of neuronal genes within or near the rearrangement. Our analysis suggests that family based studies of the combined effect of common and rare CNVs at many loci may represent a useful approach in the genetic analysis of disease susceptibility of mental disorders.
Highlights
Recent large-scale studies showed a high degree of copy number variation (CNV) in the human genome, suggesting that copy number variants (CNVs) may account for a significant proportion of human phenotypic variation and disease susceptibility [1,2,3,4,5,6]
Genotyping and CNV identification The three-generation Old Order Amish family 884 consists of individuals, including 32 clinically unaffected family members and 19 family members with affective disorders; among the 19 affected subjects, 16 have bipolar disorder type I (BPI), type II (BPII) or not otherwise specified (BP-NOS), three with major depression (MDD (Supplemental Table S1)
Structural variation including CNV constitutes a substantial portion of total genetic variability and is important in understanding the biology of common disease
Summary
Recent large-scale studies showed a high degree of copy number variation (CNV) in the human genome, suggesting that CNVs may account for a significant proportion of human phenotypic variation and disease susceptibility [1,2,3,4,5,6]. Associations with schizophrenia were found for large deletions at 1q21, 15q11.2 and 15q13.3 [11] These studies support the idea that many loci may contribute to the disease and that these genetic factors may be common for several neuropsychiatric disorders. The advantages of studying mental illness in the Old Order Amish, among others, include: (1) The families are geographically and genetically isolated, with a potentially reduced number of risk-factors for a disease compared to a more heterogeneous population; (2) Large sibships allow more direct comparisons between affected and unaffected individuals in the same family; (3) Similar environmental influences, including lack of alcohol and drug use, may minimize the potential confounding factors that contribute to disease susceptibility [17]. Subsequent genome-wide linkage analysis using 551 microsatellite markers revealed a complex mode of inheritance with possible susceptibility loci on chromosomes 6, 13 and 15 [22] and a protective locus on 4p15 [23]
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