Rare variants in TMEM132D in a case-control sample for panic disorder
Genome‐wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we...
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| Published in | American journal of medical genetics. Part B, Neuropsychiatric genetics Vol. 159B; no. 8; pp. 896 - 907 |
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| Main Authors | , , , , , , , , , |
| Format | Journal Article |
| Language | English |
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| Abstract | Genome‐wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next‐generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re‐sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next‐generation re‐sequencing in a pooled approach. Results were verified by individual re‐genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non‐synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non‐synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re‐sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders. © 2012 Wiley Periodicals, Inc. |
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| AbstractList | Genome-wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next-generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re-sequencing 40kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next-generation re-sequencing in a pooled approach. Results were verified by individual re-genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non-synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non-synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re-sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders. © 2012 Wiley Periodicals, Inc. [PUBLICATION ABSTRACT] Genome-wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next-generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re-sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next-generation re-sequencing in a pooled approach. Results were verified by individual re-genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non-synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non-synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re-sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders.Genome-wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next-generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re-sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next-generation re-sequencing in a pooled approach. Results were verified by individual re-genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non-synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non-synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re-sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders. Genome-wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next-generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re-sequencing 40kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next-generation re-sequencing in a pooled approach. Results were verified by individual re-genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non-synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non-synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re-sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders. copyright 2012 Wiley Periodicals, Inc. Genome‐wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next‐generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re‐sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next‐generation re‐sequencing in a pooled approach. Results were verified by individual re‐genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non‐synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non‐synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re‐sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders. © 2012 Wiley Periodicals, Inc. Genome-wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next-generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re-sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next-generation re-sequencing in a pooled approach. Results were verified by individual re-genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non-synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non-synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re-sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders. Genome‐wide association studies have identified common variants associated with common diseases. Most variants, however, explain only a small proportion of the estimated heritability, suggesting that rare variants might contribute to a larger extent to common diseases than assumed to date. Here, we use next‐generation sequencing to test whether such variants contribute to the risk for anxiety disorders by re‐sequencing 40 kb including all exons of the TMEM132D locus which we have previously shown to be associated with panic disorder and anxiety severity measures. DNA from 300 patients suffering from anxiety disorders, mostly panic disorder (84.7%), and 300 healthy controls was screened for the presence of genetic variants using next‐generation re‐sequencing in a pooled approach. Results were verified by individual re‐genotyping. We identified 371 variants of which 247 had not been reported before, including 15 novel non‐synonymous variants. The majority, 76% of these variants had a minor allele frequency less than 5%. While we did not identify additional common variants in TMEM132D associated with panic disorders, we observed an overrepresentation of presumably functional coding variants in healthy controls as compared to cases as well as a higher rate of private coding variants in cases, with one non‐synonymous coding variant present in four patients but not in any of the matched controls nor in over 5,500 individuals of different ethnic origins from publicly available re‐sequencing datasets. Our data suggest that not only common but also putatively functional and/or rare variants within TMEM132D might contribute to the risk to develop anxiety disorders. © 2012 Wiley Periodicals, Inc. |
| Author | Pfister, Hildegard Arloth, Janine Binder, Elisabeth B. Quast, Carina Weber, Peter Bader, Daniel Erhardt, Angelika Müller-Myhsok, Bertram Altmann, Andre Heck, Angela |
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| Keywords | rare variants Panic Nucleotide sequence next-generation sequencing Sample Anxiety disorder Check pooled DNA Case study Variant DNA Pool Sequencing SOLiD |
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| Notes | All authors have no conflict of interest to declare. ArticleID:AJMG32096 Federal Ministry of Education and Research (BMBF) ark:/67375/WNG-48GBMP0G-1 istex:7255E6A801A1B03F17CB50874A2F3E92CF8A1ECF Neuronova G GmbH. National Genome Research Network (NGFN) FKZ 01GS0481 Exzellenz-Stiftung of the Max Planck Society How to Cite this Article: Quast C, Altmann A, Weber P, Arloth J, Bader D, Heck A, Pfister H, Müller-Myhsok B, Erhardt A, Binder EB. 2012. Rare Variants in TMEM132D in a Case-Control Sample for Panic Disorder. Am J Med Genet Part B 159B:896-907. TMEM132D How to Cite this Article: Quast C, Altmann A, Weber P, Arloth J, Bader D, Heck A, Pfister H, Müller‐Myhsok B, Erhardt A, Binder EB. 2012. Rare Variants in in a Case–Control Sample for Panic Disorder. Am J Med Genet Part B 159B:896–907. ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Article-2 ObjectType-Feature-1 |
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Candidate genes of anxiety-related behavior in HAB/LAB rats and mice: Focus on vasopressin and glyoxalase-I. Neurosci Biobehav Rev 31:89-102. Pickrell JK, Marioni JC, Pai AA, Degner JF, Engelhardt BE, Nkadori E, Veyrieras JB, Stephens M, Gilad Y, Pritchard JK. 2010. Understanding mechanisms underlying human gene expression variation with RNA sequencing. Nature 464:768-772. Li H, Durbin R. 2009. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics 25:1754-1760. Rivas MA, Beaudoin M, Gardet A, Stevens 2007; 39 2010; 11 2010; 55 2009; 25 2010; 16 2010; 38 2012 2010; 107 2006; 34 2010; 464 2008; 17 2005; 62 2003; 13 2011; 32 2007; 31 2004; 305 2011; 6 2011; 5 2003; 134 2001; 40 1999 2011; 147 2010; 42 2009; 30 2009; 10 1960; 23 2011; 70 1999; 38 2011; 50 2011; 43 2007; 81 2008; 456 2009; 4 2009; 461 2005; 37 2011; 27 2008; 40 2009; 19 2010; 5 2007; 615 1959; 32 2001; 158 2009; 324 2010; 8 e_1_2_6_51_1 e_1_2_6_53_1 e_1_2_6_32_1 e_1_2_6_30_1 e_1_2_6_19_1 e_1_2_6_13_1 e_1_2_6_36_1 Bandelow B (e_1_2_6_3_1) 1999 e_1_2_6_11_1 e_1_2_6_34_1 e_1_2_6_17_1 e_1_2_6_55_1 e_1_2_6_15_1 e_1_2_6_38_1 e_1_2_6_43_1 e_1_2_6_20_1 e_1_2_6_41_1 e_1_2_6_9_1 e_1_2_6_5_1 e_1_2_6_7_1 e_1_2_6_24_1 e_1_2_6_49_1 e_1_2_6_22_1 e_1_2_6_28_1 e_1_2_6_45_1 e_1_2_6_26_1 e_1_2_6_47_1 e_1_2_6_52_1 e_1_2_6_54_1 e_1_2_6_10_1 e_1_2_6_31_1 e_1_2_6_50_1 e_1_2_6_14_1 e_1_2_6_35_1 e_1_2_6_12_1 e_1_2_6_33_1 e_1_2_6_18_1 e_1_2_6_39_1 e_1_2_6_56_1 e_1_2_6_16_1 e_1_2_6_37_1 e_1_2_6_42_1 e_1_2_6_21_1 e_1_2_6_40_1 e_1_2_6_8_1 e_1_2_6_4_1 e_1_2_6_6_1 e_1_2_6_25_1 e_1_2_6_48_1 e_1_2_6_23_1 e_1_2_6_2_1 e_1_2_6_29_1 e_1_2_6_44_1 e_1_2_6_27_1 e_1_2_6_46_1 |
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| SubjectTerms | Adult and adolescent clinical studies Agoraphobia - genetics anxiety disorder Anxiety disorders. Neuroses Biological and medical sciences Case-Control Studies Female Gene Frequency Genetic Predisposition to Disease Genetic Variation Genetics Genome-Wide Association Study Genotype High-Throughput Nucleotide Sequencing Humans Male Medical genetics Medical sciences Membrane Proteins - genetics next-generation sequencing Panic disorder Panic Disorder - genetics Phobic Disorders - genetics Polymorphism, Single Nucleotide pooled DNA Psychology. Psychoanalysis. Psychiatry Psychopathology. Psychiatry rare variants Sequence Analysis, DNA SOLiD |
| Title | Rare variants in TMEM132D in a case-control sample for panic disorder |
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