Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin

Stephanie Nissen; Sherri Liang; Tatyana Shehktman; John R. Kelsoe; John R. Kelsoe; Tiffany A. Greenwood; Caroline M. Nievergelt; Rebecca McKinney; Paul D. Shilling; Erin N. Smith; Nicholas J. Schork; Cinnamon S. Bloss; John I. Nurnberger; Howard J. Edenberg; Tatiana Foroud; Daniel L. Koller; Elliot S. Gershon; Chunyu Liu; Judith A. Badner; William A. Scheftner; William B. Lawson; Evaristus A. Nwulia; Maria Hipolito; William Coryell; John Rice; William Byerley; Francis J. McMahon; Wade H. Berrettini; James B. Potash; Peter P. Zandi; Pamela B. Mahon; Melvin G. McInnis; Sebastian Zöllner; Peng Zhang; David W. Craig; Szabolics Szelinger; Thomas B. Barrett; Thomas G. Schulze

doi:10.1002/ajmg.b.32099

Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin

Stephanie Nissen, Sherri Liang, Tatyana Shehktman, John R. Kelsoe, John R. Kelsoe, Tiffany A. Greenwood, Caroline M. Nievergelt, Rebecca McKinney, Paul D. Shilling, Erin N. Smith, Nicholas J. Schork, Cinnamon S. Bloss, John I. Nurnberger, Howard J. Edenberg, Tatiana Foroud, Daniel L. Koller, Elliot S. Gershon, Chunyu Liu, Judith A. Badner, William A. ScheftnerWilliam B. Lawson, Evaristus A. Nwulia, Maria Hipolito, William Coryell, John Rice, William Byerley, Francis J. McMahon, Wade H. Berrettini, James B. Potash, Peter P. Zandi, Pamela B. Mahon, Melvin G. McInnis, Sebastian Zöllner, Peng Zhang, David W. Craig, Szabolics Szelinger, Thomas B. Barrett, Thomas G. Schulze

School of Medicine

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P=4.69×10^-4). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P=1.42×10^-5). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P=8.89×10^-6). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P=3.43×10^-4). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P=1.76×10^-6). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region.

Original language	English (US)
Pages (from-to)	941-950
Number of pages	10
Journal	American Journal of Medical Genetics - Neuropsychiatric Genetics
Volume	159 B
Issue number	8
DOIs	https://doi.org/10.1002/ajmg.b.32099
State	Published - Dec 2012

Keywords

Bipolar disorder
Chromosome 22
Genetic association
Stargazin

ASJC Scopus subject areas

Genetics(clinical)
Psychiatry and Mental health
Cellular and Molecular Neuroscience

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Nissen, S., Liang, S., Shehktman, T., Kelsoe, J. R., Kelsoe, J. R., Greenwood, T. A., Nievergelt, C. M., McKinney, R., Shilling, P. D., Smith, E. N., Schork, N. J., Bloss, C. S., Nurnberger, J. I., Edenberg, H. J., Foroud, T., Koller, D. L., Gershon, E. S., Liu, C., Badner, J. A., ... Schulze, T. G. (2012). Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin. American Journal of Medical Genetics - Neuropsychiatric Genetics, 159 B(8), 941-950. https://doi.org/10.1002/ajmg.b.32099

Nissen, S, Liang, S, Shehktman, T, Kelsoe, JR, Kelsoe, JR, Greenwood, TA, Nievergelt, CM, McKinney, R, Shilling, PD, Smith, EN, Schork, NJ, Bloss, CS, Nurnberger, JI, Edenberg, HJ, Foroud, T, Koller, DL, Gershon, ES, Liu, C, Badner, JA, Scheftner, WA, Lawson, WB, Nwulia, EA, Hipolito, M, Coryell, W, Rice, J, Byerley, W, McMahon, FJ, Berrettini, WH, Potash, JB, Zandi, PP, Mahon, PB, McInnis, MG, Zöllner, S, Zhang, P, Craig, DW, Szelinger, S, Barrett, TB & Schulze, TG 2012, 'Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin', American Journal of Medical Genetics - Neuropsychiatric Genetics, vol. 159 B, no. 8, pp. 941-950. https://doi.org/10.1002/ajmg.b.32099

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title = "Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin",

abstract = "We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P=4.69×10-4). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P=1.42×10-5). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P=8.89×10-6). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P=3.43×10-4). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P=1.76×10-6). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region.",

keywords = "Bipolar disorder, Chromosome 22, Genetic association, Stargazin",

author = "Stephanie Nissen and Sherri Liang and Tatyana Shehktman and Kelsoe, {John R.} and Kelsoe, {John R.} and Greenwood, {Tiffany A.} and Nievergelt, {Caroline M.} and Rebecca McKinney and Shilling, {Paul D.} and Smith, {Erin N.} and Schork, {Nicholas J.} and Bloss, {Cinnamon S.} and Nurnberger, {John I.} and Edenberg, {Howard J.} and Tatiana Foroud and Koller, {Daniel L.} and Gershon, {Elliot S.} and Chunyu Liu and Badner, {Judith A.} and Scheftner, {William A.} and Lawson, {William B.} and Nwulia, {Evaristus A.} and Maria Hipolito and William Coryell and John Rice and William Byerley and McMahon, {Francis J.} and Berrettini, {Wade H.} and Potash, {James B.} and Zandi, {Peter P.} and Mahon, {Pamela B.} and McInnis, {Melvin G.} and Sebastian Z{\"o}llner and Peng Zhang and Craig, {David W.} and Szabolics Szelinger and Barrett, {Thomas B.} and Schulze, {Thomas G.}",

year = "2012",

month = dec,

doi = "10.1002/ajmg.b.32099",

language = "English (US)",

volume = "159 B",

pages = "941--950",

journal = "American Journal of Medical Genetics - Neuropsychiatric Genetics",

issn = "1552-4841",

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T1 - Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin

AU - Nissen, Stephanie

AU - Liang, Sherri

AU - Shehktman, Tatyana

AU - Kelsoe, John R.

AU - Greenwood, Tiffany A.

AU - Nievergelt, Caroline M.

AU - McKinney, Rebecca

AU - Shilling, Paul D.

AU - Smith, Erin N.

AU - Schork, Nicholas J.

AU - Bloss, Cinnamon S.

AU - Nurnberger, John I.

AU - Edenberg, Howard J.

AU - Foroud, Tatiana

AU - Koller, Daniel L.

AU - Gershon, Elliot S.

AU - Liu, Chunyu

AU - Badner, Judith A.

AU - Scheftner, William A.

AU - Lawson, William B.

AU - Nwulia, Evaristus A.

AU - Hipolito, Maria

AU - Coryell, William

AU - Rice, John

AU - Byerley, William

AU - McMahon, Francis J.

AU - Berrettini, Wade H.

AU - Potash, James B.

AU - Zandi, Peter P.

AU - Mahon, Pamela B.

AU - McInnis, Melvin G.

AU - Zöllner, Sebastian

AU - Zhang, Peng

AU - Craig, David W.

AU - Szelinger, Szabolics

AU - Barrett, Thomas B.

AU - Schulze, Thomas G.

PY - 2012/12

Y1 - 2012/12

N2 - We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P=4.69×10-4). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P=1.42×10-5). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P=8.89×10-6). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P=3.43×10-4). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P=1.76×10-6). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region.

AB - We have previously reported genome-wide significant linkage of bipolar disorder to a region on 22q12.3 near the marker D22S278. Towards identifying the susceptibility gene, we have conducted a fine-mapping association study of the region in two independent family samples, an independent case-control sample and a genome-wide association dataset. Two hundred SNPs were first examined in a 5Mb region surrounding the D22S278 marker in a sample of 169 families and analyzed using PLINK. The peak of association was a haplotype near the genes stargazin (CACNG2), intraflagellar transport protein homolog 27 (IFT27) and parvalbumin (PVALB; P=4.69×10-4). This peak overlapped a significant haplotype in a family based association study of a second independent sample of 294 families (P=1.42×10-5). Analysis of the combined family sample yielded statistically significant evidence of association to a rare three SNP haplotype in the gene IFT27 (P=8.89×10-6). Twelve SNPs comprising these haplotypes were genotyped in an independent sample of 574 bipolar I cases and 550 controls. Statistically significant association was found for a haplotype window that overlapped the region from the first two family samples (P=3.43×10-4). However, analyses of the two family samples using the program LAMP, found no evidence for association in this region, but did yield significant evidence for association to a haplotype 3' of CACNG2 (P=1.76×10-6). Furthermore, no evidence for association was found in a large genome-wide association dataset. The replication of association to overlapping haplotypes in three independent datasets suggests the presence of a bipolar disorder susceptibility gene in this region.

KW - Bipolar disorder

KW - Chromosome 22

KW - Genetic association

KW - Stargazin

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VL - 159 B

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JO - American Journal of Medical Genetics - Neuropsychiatric Genetics

JF - American Journal of Medical Genetics - Neuropsychiatric Genetics

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Evidence for association of bipolar disorder to haplotypes in the 22q12.3 region near the genes stargazin, ift27 and parvalbumin

Abstract

Keywords

ASJC Scopus subject areas

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