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Genomic landscape of a three-generation pedigree segregating affective disorder.

Yang S, Wang K, Gregory B, Berrettini W, Wang LS, Hakonarson H, Bucan M - PLoS ONE (2009)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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.

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Related in: MedlinePlus

Validation of CNVs by QPCR in 51 individuals.The copy numbers detected by QPCR (bars) and PennCNV (circles) were plotted against all individuals in family 884 (only the last four digits of the cell line IDs were shown). Black bars or circles indicate affected individuals (including BPI, BPII, BP-NOS and MDD), white bars or circles indicate unaffected individuals. Note that the PennCNV calls were absent for subjects 5906, 5968, 5970, 6006, and 6024.
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pone-0004474-g002: Validation of CNVs by QPCR in 51 individuals.The copy numbers detected by QPCR (bars) and PennCNV (circles) were plotted against all individuals in family 884 (only the last four digits of the cell line IDs were shown). Black bars or circles indicate affected individuals (including BPI, BPII, BP-NOS and MDD), white bars or circles indicate unaffected individuals. Note that the PennCNV calls were absent for subjects 5906, 5968, 5970, 6006, and 6024.

Mentions: To experimentally validate the CNVs at a genomic level, we randomly selected 6 CNV regions (at 4p12, 4q13.2, 6q14.1, 6q27, 12p13.31, and 15q14; Table 1) and examined their copy number by real-time quantitative PCR (QPCR) in fibroblasts or LCLs from 51 Amish family members. The QPCR experiment confirmed the presence of these deletions or duplications in all subjects (Figure 2). Our results indicate that the CNVs detected by computational analysis of SNP genotyping data are highly reliable. Moreover, 19 CNVs were detected in family members across three generations and they were inherited in a Mendelian fashion with identical boundaries, suggesting that these variants are genetically stable.


Genomic landscape of a three-generation pedigree segregating affective disorder.

Yang S, Wang K, Gregory B, Berrettini W, Wang LS, Hakonarson H, Bucan M - PLoS ONE (2009)

Validation of CNVs by QPCR in 51 individuals.The copy numbers detected by QPCR (bars) and PennCNV (circles) were plotted against all individuals in family 884 (only the last four digits of the cell line IDs were shown). Black bars or circles indicate affected individuals (including BPI, BPII, BP-NOS and MDD), white bars or circles indicate unaffected individuals. Note that the PennCNV calls were absent for subjects 5906, 5968, 5970, 6006, and 6024.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2637422&req=5

pone-0004474-g002: Validation of CNVs by QPCR in 51 individuals.The copy numbers detected by QPCR (bars) and PennCNV (circles) were plotted against all individuals in family 884 (only the last four digits of the cell line IDs were shown). Black bars or circles indicate affected individuals (including BPI, BPII, BP-NOS and MDD), white bars or circles indicate unaffected individuals. Note that the PennCNV calls were absent for subjects 5906, 5968, 5970, 6006, and 6024.
Mentions: To experimentally validate the CNVs at a genomic level, we randomly selected 6 CNV regions (at 4p12, 4q13.2, 6q14.1, 6q27, 12p13.31, and 15q14; Table 1) and examined their copy number by real-time quantitative PCR (QPCR) in fibroblasts or LCLs from 51 Amish family members. The QPCR experiment confirmed the presence of these deletions or duplications in all subjects (Figure 2). Our results indicate that the CNVs detected by computational analysis of SNP genotyping data are highly reliable. Moreover, 19 CNVs were detected in family members across three generations and they were inherited in a Mendelian fashion with identical boundaries, suggesting that these variants are genetically stable.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.

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.

Show MeSH
Related in: MedlinePlus