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1. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author: Bradfield, Jonathan P., Kember, Rachel L., Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M., Bell, Joshua A., Broadaway, K. Alaine, Chen, Zhanghua, Chai, Jin Fang, Davies, Neil M., Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M., Have, Christian Theil, Strachan, David P., Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H., Wang, Carol A., Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W. James, Glessner, Joseph T., Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L., Guxens, Mònica, Felix, Janine F., Hansen, Torben, Jaddoe, Vincent W.V., Perry, John R.B., Rivadeneira, Fernando, Bradfield, Jonathan P., Kember, Rachel L., Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M., Bell, Joshua A., Broadaway, K. Alaine, Chen, Zhanghua, Chai, Jin Fang, Davies, Neil M., Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M., Have, Christian Theil, Strachan, David P., Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H., Wang, Carol A., Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W. James, Glessner, Joseph T., Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L., Guxens, Mònica, Felix, Janine F., Hansen, Torben, Jaddoe, Vincent W.V., Perry, John R.B., and Rivadeneira, Fernando
Abstract: BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation. CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.
Published: 2024

2. Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations

Author: Lennon, Niall J., Kottyan, Leah C., Kachulis, Christopher, Abul-Husn, Noura S., Arias, Josh, Belbin, Gillian, Below, Jennifer E., Berndt, Sonja I., Chung, Wendy K., Cimino, James J., Clayton, Ellen Wright, Connolly, John J., Crosslin, David R., Dikilitas, Ozan, Velez Edwards, Digna R., Feng, Qi Ping, Fisher, Marissa, Freimuth, Robert R., Ge, Tian, Glessner, Joseph T., Gordon, Adam S., Patterson, Candace, Hakonarson, Hakon, Harden, Maegan, Harr, Margaret, Hirschhorn, Joel, Hoggart, Clive, Hsu, Li, Irvin, Marguerite R., Jarvik, Gail P., Karlson, Elizabeth W., Khan, Atlas, Khera, Amit, Kiryluk, Krzysztof, Kullo, Iftikhar, Larkin, Katie, Limdi, Nita, Linder, Jodell E., Loos, Ruth, Luo, Yuan, Malolepsza, Edyta, Manolio, Teri A., Martin, Lisa J., McCarthy, Li, McNally, Elizabeth M., Meigs, James B., Mersha, Tesfaye B., Mosley, Jonathan D., Musick, Anjene, Namjou, Bahram, Pai, Nihal, Pesce, Lorenzo L., Peters, Ulrike, Peterson, Josh F., Prows, Cynthia A., Puckelwartz, Megan J., Rehm, Heidi L., Roden, Dan M., Rosenthal, Elisabeth A., Rowley, Robb, Sawicki, Konrad Teodor, Schaid, Daniel J., Smit, Roelof A.J., Smith, Johanna L., Smoller, Jordan W., Thomas, Minta, Tiwari, Hemant, Toledo, Diana M., Vaitinadin, Nataraja Sarma, Veenstra, David, Walunas, Theresa L., Wang, Zhe, Wei, Wei Qi, Weng, Chunhua, Wiesner, Georgia L., Yin, Xianyong, Kenny, Eimear E., Berndt, Sonja, Lennon, Niall J., Kottyan, Leah C., Kachulis, Christopher, Abul-Husn, Noura S., Arias, Josh, Belbin, Gillian, Below, Jennifer E., Berndt, Sonja I., Chung, Wendy K., Cimino, James J., Clayton, Ellen Wright, Connolly, John J., Crosslin, David R., Dikilitas, Ozan, Velez Edwards, Digna R., Feng, Qi Ping, Fisher, Marissa, Freimuth, Robert R., Ge, Tian, Glessner, Joseph T., Gordon, Adam S., Patterson, Candace, Hakonarson, Hakon, Harden, Maegan, Harr, Margaret, Hirschhorn, Joel, Hoggart, Clive, Hsu, Li, Irvin, Marguerite R., Jarvik, Gail P., Karlson, Elizabeth W., Khan, Atlas, Khera, Amit, Kiryluk, Krzysztof, Kullo, Iftikhar, Larkin, Katie, Limdi, Nita, Linder, Jodell E., Loos, Ruth, Luo, Yuan, Malolepsza, Edyta, Manolio, Teri A., Martin, Lisa J., McCarthy, Li, McNally, Elizabeth M., Meigs, James B., Mersha, Tesfaye B., Mosley, Jonathan D., Musick, Anjene, Namjou, Bahram, Pai, Nihal, Pesce, Lorenzo L., Peters, Ulrike, Peterson, Josh F., Prows, Cynthia A., Puckelwartz, Megan J., Rehm, Heidi L., Roden, Dan M., Rosenthal, Elisabeth A., Rowley, Robb, Sawicki, Konrad Teodor, Schaid, Daniel J., Smit, Roelof A.J., Smith, Johanna L., Smoller, Jordan W., Thomas, Minta, Tiwari, Hemant, Toledo, Diana M., Vaitinadin, Nataraja Sarma, Veenstra, David, Walunas, Theresa L., Wang, Zhe, Wei, Wei Qi, Weng, Chunhua, Wiesner, Georgia L., Yin, Xianyong, Kenny, Eimear E., and Berndt, Sonja
Abstract: Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.
Published: 2024

3. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author: Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, Cousminer, Diana L, Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, and Cousminer, Diana L
Abstract: Background: Pubertal growth patterns correlate with future health outcomes. How‑ever, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Transla‑tion And Rotation (SITAR) growth curve analysis on~56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analy‑ses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results: Large-scale growth modeling enables an unprecedented view of adoles‑ cent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide signifcant loci and leverage trans-ancestry data to perform fnemapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with diferent growth trajectories correlated with dif‑ferent outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fbrillation. Conclusion: We report novel genetic associations with the tempo of pubertal growth and fnd that genetic determinants of growth are correlated with reproductive, glyce‑mic, respiratory, and cardiac traits in adulthood. These results aid in identifying specifc growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern., BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.
Published: 2024

4. Selection, optimization and validation of ten chronic disease polygenic risk scores for clinical implementation in diverse US populations

Author: Lennon, Niall J., Kottyan, Leah C., Kachulis, Christopher, Abul-Husn, Noura S., Arias, Josh, Belbin, Gillian, Below, Jennifer E., Berndt, Sonja I., Chung, Wendy K., Cimino, James J., Clayton, Ellen Wright, Connolly, John J., Crosslin, David R., Dikilitas, Ozan, Velez Edwards, Digna R., Feng, Qi Ping, Fisher, Marissa, Freimuth, Robert R., Ge, Tian, Glessner, Joseph T., Gordon, Adam S., Patterson, Candace, Hakonarson, Hakon, Harden, Maegan, Harr, Margaret, Hirschhorn, Joel, Hoggart, Clive, Hsu, Li, Irvin, Marguerite R., Jarvik, Gail P., Karlson, Elizabeth W., Khan, Atlas, Khera, Amit, Kiryluk, Krzysztof, Kullo, Iftikhar, Larkin, Katie, Limdi, Nita, Linder, Jodell E., Loos, Ruth, Luo, Yuan, Malolepsza, Edyta, Manolio, Teri A., Martin, Lisa J., McCarthy, Li, McNally, Elizabeth M., Meigs, James B., Mersha, Tesfaye B., Mosley, Jonathan D., Musick, Anjene, Namjou, Bahram, Pai, Nihal, Pesce, Lorenzo L., Peters, Ulrike, Peterson, Josh F., Prows, Cynthia A., Puckelwartz, Megan J., Rehm, Heidi L., Roden, Dan M., Rosenthal, Elisabeth A., Rowley, Robb, Sawicki, Konrad Teodor, Schaid, Daniel J., Smit, Roelof A.J., Smith, Johanna L., Smoller, Jordan W., Thomas, Minta, Tiwari, Hemant, Toledo, Diana M., Vaitinadin, Nataraja Sarma, Veenstra, David, Walunas, Theresa L., Wang, Zhe, Wei, Wei Qi, Weng, Chunhua, Wiesner, Georgia L., Yin, Xianyong, Kenny, Eimear E., Berndt, Sonja, Lennon, Niall J., Kottyan, Leah C., Kachulis, Christopher, Abul-Husn, Noura S., Arias, Josh, Belbin, Gillian, Below, Jennifer E., Berndt, Sonja I., Chung, Wendy K., Cimino, James J., Clayton, Ellen Wright, Connolly, John J., Crosslin, David R., Dikilitas, Ozan, Velez Edwards, Digna R., Feng, Qi Ping, Fisher, Marissa, Freimuth, Robert R., Ge, Tian, Glessner, Joseph T., Gordon, Adam S., Patterson, Candace, Hakonarson, Hakon, Harden, Maegan, Harr, Margaret, Hirschhorn, Joel, Hoggart, Clive, Hsu, Li, Irvin, Marguerite R., Jarvik, Gail P., Karlson, Elizabeth W., Khan, Atlas, Khera, Amit, Kiryluk, Krzysztof, Kullo, Iftikhar, Larkin, Katie, Limdi, Nita, Linder, Jodell E., Loos, Ruth, Luo, Yuan, Malolepsza, Edyta, Manolio, Teri A., Martin, Lisa J., McCarthy, Li, McNally, Elizabeth M., Meigs, James B., Mersha, Tesfaye B., Mosley, Jonathan D., Musick, Anjene, Namjou, Bahram, Pai, Nihal, Pesce, Lorenzo L., Peters, Ulrike, Peterson, Josh F., Prows, Cynthia A., Puckelwartz, Megan J., Rehm, Heidi L., Roden, Dan M., Rosenthal, Elisabeth A., Rowley, Robb, Sawicki, Konrad Teodor, Schaid, Daniel J., Smit, Roelof A.J., Smith, Johanna L., Smoller, Jordan W., Thomas, Minta, Tiwari, Hemant, Toledo, Diana M., Vaitinadin, Nataraja Sarma, Veenstra, David, Walunas, Theresa L., Wang, Zhe, Wei, Wei Qi, Weng, Chunhua, Wiesner, Georgia L., Yin, Xianyong, Kenny, Eimear E., and Berndt, Sonja
Abstract: Polygenic risk scores (PRSs) have improved in predictive performance, but several challenges remain to be addressed before PRSs can be implemented in the clinic, including reduced predictive performance of PRSs in diverse populations, and the interpretation and communication of genetic results to both providers and patients. To address these challenges, the National Human Genome Research Institute-funded Electronic Medical Records and Genomics (eMERGE) Network has developed a framework and pipeline for return of a PRS-based genome-informed risk assessment to 25,000 diverse adults and children as part of a clinical study. From an initial list of 23 conditions, ten were selected for implementation based on PRS performance, medical actionability and potential clinical utility, including cardiometabolic diseases and cancer. Standardized metrics were considered in the selection process, with additional consideration given to strength of evidence in African and Hispanic populations. We then developed a pipeline for clinical PRS implementation (score transfer to a clinical laboratory, validation and verification of score performance), and used genetic ancestry to calibrate PRS mean and variance, utilizing genetically diverse data from 13,475 participants of the All of Us Research Program cohort to train and test model parameters. Finally, we created a framework for regulatory compliance and developed a PRS clinical report for return to providers and for inclusion in an additional genome-informed risk assessment. The initial experience from eMERGE can inform the approach needed to implement PRS-based testing in diverse clinical settings.
Published: 2024

5. Trans-ancestral genome-wide association study of longitudinal pubertal height growth and shared heritability with adult health outcomes

Author: Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, Cousminer, Diana L, Bradfield, Jonathan P, Kember, Rachel L, Ulrich, Anna, Balkiyarova, Zhanna, Alyass, Akram, Aris, Izzuddin M, Bell, Joshua A, Broadaway, K Alaine, Chen, Zhanghua, Chai, Jin-Fang, Davies, Neil M, Fernandez-Orth, Dietmar, Bustamante, Mariona, Fore, Ruby, Ganguli, Amitavo, Heiskala, Anni, Hottenga, Jouke-Jan, Íñiguez, Carmen, Kobes, Sayuko, Leinonen, Jaakko, Lowry, Estelle, Lyytikainen, Leo-Pekka, Mahajan, Anubha, Pitkänen, Niina, Schnurr, Theresia M, Have, Christian Theil, Strachan, David P, Thiering, Elisabeth, Vogelezang, Suzanne, Wade, Kaitlin H, Wang, Carol A, Wong, Andrew, Holm, Louise Aas, Chesi, Alessandra, Choong, Catherine, Cruz, Miguel, Elliott, Paul, Franks, Steve, Frithioff-Bøjsøe, Christine, Gauderman, W James, Glessner, Joseph T, Gilsanz, Vicente, Griesman, Kendra, Hanson, Robert L, Kaakinen, Marika, Kalkwarf, Heidi, Kelly, Andrea, Hansen, Torben, Holm, Jens-Christian, Sørensen, Thorkild I A, Grant, Struan F A, and Cousminer, Diana L
Abstract: Background: Pubertal growth patterns correlate with future health outcomes. How‑ever, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Transla‑tion And Rotation (SITAR) growth curve analysis on~56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analy‑ses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank. Results: Large-scale growth modeling enables an unprecedented view of adoles‑ cent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide signifcant loci and leverage trans-ancestry data to perform fnemapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with diferent growth trajectories correlated with dif‑ferent outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fbrillation. Conclusion: We report novel genetic associations with the tempo of pubertal growth and fnd that genetic determinants of growth are correlated with reproductive, glyce‑mic, respiratory, and cardiac traits in adulthood. These results aid in identifying specifc growth trajectories impacting lifelong health and show that there may not be a single “optimal” pubertal growth pattern., BACKGROUND: Pubertal growth patterns correlate with future health outcomes. However, the genetic mechanisms mediating growth trajectories remain largely unknown. Here, we modeled longitudinal height growth with Super-Imposition by Translation And Rotation (SITAR) growth curve analysis on ~ 56,000 trans-ancestry samples with repeated height measurements from age 5 years to adulthood. We performed genetic analysis on six phenotypes representing the magnitude, timing, and intensity of the pubertal growth spurt. To investigate the lifelong impact of genetic variants associated with pubertal growth trajectories, we performed genetic correlation analyses and phenome-wide association studies in the Penn Medicine BioBank and the UK Biobank.RESULTS: Large-scale growth modeling enables an unprecedented view of adolescent growth across contemporary and 20th-century pediatric cohorts. We identify 26 genome-wide significant loci and leverage trans-ancestry data to perform fine-mapping. Our data reveals genetic relationships between pediatric height growth and health across the life course, with different growth trajectories correlated with different outcomes. For instance, a faster tempo of pubertal growth correlates with higher bone mineral density, HOMA-IR, fasting insulin, type 2 diabetes, and lung cancer, whereas being taller at early puberty, taller across puberty, and having quicker pubertal growth were associated with higher risk for atrial fibrillation.CONCLUSION: We report novel genetic associations with the tempo of pubertal growth and find that genetic determinants of growth are correlated with reproductive, glycemic, respiratory, and cardiac traits in adulthood. These results aid in identifying specific growth trajectories impacting lifelong health and show that there may not be a single "optimal" pubertal growth pattern.
Published: 2024

6. Genomic Disorders in CKD across the Lifespan

Author: Verbitsky, Miguel, Krishnamurthy, Sarathbabu, Krithivasan, Priya, Hughes, Daniel, Khan, Atlas, Marasà, Maddalena, Vena, Natalie, Khosla, Pavan, Zhang, Junying, Lim, Tze Y., Glessner, Joseph T., Weng, Chunhua, Shang, Ning, Shen, Yufeng, Hripcsak, George, Hakonarson, Hakon, Ionita-Laza, Iuliana, Levy, Brynn, Kenny, Eimear E., Loos, Ruth J.F., Kiryluk, Krzysztof, Sanna-Cherchi, Simone, Crosslin, David R., Furth, Susan, Warady, Bradley A., Igo, Robert P., Iyengar, Sudha K., Wong, Craig S., Parsa, Afshin, Feldman, Harold I., Gharavi, Ali G., Verbitsky, Miguel, Krishnamurthy, Sarathbabu, Krithivasan, Priya, Hughes, Daniel, Khan, Atlas, Marasà, Maddalena, Vena, Natalie, Khosla, Pavan, Zhang, Junying, Lim, Tze Y., Glessner, Joseph T., Weng, Chunhua, Shang, Ning, Shen, Yufeng, Hripcsak, George, Hakonarson, Hakon, Ionita-Laza, Iuliana, Levy, Brynn, Kenny, Eimear E., Loos, Ruth J.F., Kiryluk, Krzysztof, Sanna-Cherchi, Simone, Crosslin, David R., Furth, Susan, Warady, Bradley A., Igo, Robert P., Iyengar, Sudha K., Wong, Craig S., Parsa, Afshin, Feldman, Harold I., and Gharavi, Ali G.
Abstract: SIGNIFICANCE STATEMENT: Pathogenic structural genetic variants, also known as genomic disorders, have been associated with pediatric CKD. This study extends those results across the lifespan, with genomic disorders enriched in both pediatric and adult patients compared with controls. In the Chronic Renal Insufficiency Cohort study, genomic disorders were also associated with lower serum Mg, lower educational performance, and a higher risk of death. A phenome-wide association study confirmed the link between kidney disease and genomic disorders in an unbiased way. Systematic detection of genomic disorders can provide a molecular diagnosis and refine prediction of risk and prognosis. BACKGROUND: Genomic disorders (GDs) are associated with many comorbid outcomes, including CKD. Identification of GDs has diagnostic utility. METHODS: We examined the prevalence of GDs among participants in the Chronic Kidney Disease in Children (CKiD) cohort II ( n =248), Chronic Renal Insufficiency Cohort (CRIC) study ( n =3375), Columbia University CKD Biobank (CU-CKD; n =1986), and the Family Investigation of Nephropathy and Diabetes (FIND; n =1318) compared with 30,746 controls. We also performed a phenome-wide association analysis (PheWAS) of GDs in the electronic MEdical Records and GEnomics (eMERGE; n =11,146) cohort. RESULTS: We found nine out of 248 (3.6%) CKiD II participants carried a GD, replicating prior findings in pediatric CKD. We also identified GDs in 72 out of 6679 (1.1%) adult patients with CKD in the CRIC, CU-CKD, and FIND cohorts, compared with 199 out of 30,746 (0.65%) GDs in controls (OR, 1.7; 95% CI, 1.3 to 2.2). Among adults with CKD, we found recurrent GDs at the 1q21.1, 16p11.2, 17q12, and 22q11.2 loci. The 17q12 GD (diagnostic of renal cyst and diabetes syndrome) was most frequent, present in 1:252 patients with CKD and diabetes. In the PheWAS, dialysis and neuropsychiatric phenotypes were the top associations with GDs. In CRIC participants, GDs were associ
Published: 2023

7. A cross-disorder dosage sensitivity map of the human genome

Author: Collins, Ryan L., Glessner, Joseph T., Porcu, Eleonora, Lepamets, Maarja, Brandon, Rhonda, Lauricella, Christopher, Han, Lide, Morley, Theodore, Niestroj, Lisa-Marie, Ulirsch, Jacob, Everett, Selin, Howrigan, Daniel P., Boone, Philip M., Fu, Jack, Karczewski, Konrad J., Kellaris, Georgios, Lowther, Chelsea, Lucente, Diane, Mohajeri, Kiana, Noukas, Margit, Nuttle, Xander, Samocha, Kaitlin E., Trinh, Mi, Ullah, Farid, Vosa, Urmo, Hurles, Matthew E., Aradhya, Swaroop, Davis, Erica E., Finucane, Hilary, Gusella, James F., Janze, Aura, Katsanis, Nicholas, Matyakhina, Ludmila, Neale, Benjamin M., Sanders, David, Warren, Stephanie, Hodge, Jennelle C., Lal, Dennis, Ruderfer, Douglas M., Meck, Jeanne, Magi, Reedik, Esko, Tonu, Reymond, Alexandre, Kutalik, Zoltan, Hakonarson, Hakon, Sunyaev, Shamil, Brand, Harrison, Talkowski, Michael E., Collins, Ryan L., Glessner, Joseph T., Porcu, Eleonora, Lepamets, Maarja, Brandon, Rhonda, Lauricella, Christopher, Han, Lide, Morley, Theodore, Niestroj, Lisa-Marie, Ulirsch, Jacob, Everett, Selin, Howrigan, Daniel P., Boone, Philip M., Fu, Jack, Karczewski, Konrad J., Kellaris, Georgios, Lowther, Chelsea, Lucente, Diane, Mohajeri, Kiana, Noukas, Margit, Nuttle, Xander, Samocha, Kaitlin E., Trinh, Mi, Ullah, Farid, Vosa, Urmo, Hurles, Matthew E., Aradhya, Swaroop, Davis, Erica E., Finucane, Hilary, Gusella, James F., Janze, Aura, Katsanis, Nicholas, Matyakhina, Ludmila, Neale, Benjamin M., Sanders, David, Warren, Stephanie, Hodge, Jennelle C., Lal, Dennis, Ruderfer, Douglas M., Meck, Jeanne, Magi, Reedik, Esko, Tonu, Reymond, Alexandre, Kutalik, Zoltan, Hakonarson, Hakon, Sunyaev, Shamil, Brand, Harrison, and Talkowski, Michael E.
Abstract: Rare copy-number variants (rCNVs) include deletions and duplications that occur infrequently in the global human population and can confer substantial risk for disease. In this study, we aimed to quantify the prop-erties of haploinsufficiency (i.e., deletion intolerance) and triplosensitivity (i.e., duplication intolerance) throughout the human genome. We harmonized and meta-analyzed rCNVs from nearly one million individuals to construct a genome-wide catalog of dosage sensitivity across 54 disorders, which defined 163 dosage sensitive segments associated with at least one disorder. These segments were typically gene dense and often harbored dominant dosage sensitive driver genes, which we were able to prioritize using statistical fine-mapping. Finally, we designed an ensemble machine-learning model to predict probabilities of dosage sensitivity (pHaplo & pTriplo) for all autosomal genes, which identified 2,987 haploinsufficient and 1,559 trip-losensitive genes, including 648 that were uniquely triplosensitive. This dosage sensitivity resource will pro-vide broad utility for human disease research and clinical genetics.
Published: 2022

8. Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Author: Li, Yun Rose, Glessner, Joseph T, Coe, Bradley P, Li, Jin, Mohebnasab, Maede, Chang, Xiao, Connolly, John, Kao, Charlly, Wei, Zhi, Bradfield, Jonathan, Kim, Cecilia, Hou, Cuiping, Khan, Munir, Mentch, Frank, Qiu, Haijun, Bakay, Marina, Cardinale, Christopher, Lemma, Maria, Abrams, Debra, Bridglall-Jhingoor, Andrew, Behr, Meckenzie, Harrison, Shanell, Otieno, George, Thomas, Alexandria, Wang, Fengxiang, Chiavacci, Rosetta, Wu, Lawrence, Hadley, Dexter, Goldmuntz, Elizabeth, Elia, Josephine, Maris, John, Grundmeier, Robert, Devoto, Marcella, Keating, Brendan, March, Michael, Pellagrino, Renata, Grant, Struan FA, Sleiman, Patrick MA, Li, Mingyao, Eichler, Evan E, Hakonarson, Hakon, Li, Yun Rose, Glessner, Joseph T, Coe, Bradley P, Li, Jin, Mohebnasab, Maede, Chang, Xiao, Connolly, John, Kao, Charlly, Wei, Zhi, Bradfield, Jonathan, Kim, Cecilia, Hou, Cuiping, Khan, Munir, Mentch, Frank, Qiu, Haijun, Bakay, Marina, Cardinale, Christopher, Lemma, Maria, Abrams, Debra, Bridglall-Jhingoor, Andrew, Behr, Meckenzie, Harrison, Shanell, Otieno, George, Thomas, Alexandria, Wang, Fengxiang, Chiavacci, Rosetta, Wu, Lawrence, Hadley, Dexter, Goldmuntz, Elizabeth, Elia, Josephine, Maris, John, Grundmeier, Robert, Devoto, Marcella, Keating, Brendan, March, Michael, Pellagrino, Renata, Grant, Struan FA, Sleiman, Patrick MA, Li, Mingyao, Eichler, Evan E, and Hakonarson, Hakon
Abstract: Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.
Published: 2019

9. Rare copy number variants in over 100,000 European ancestry subjects reveal multiple disease associations.

Author: Li, Yun Rose, Glessner, Joseph T, Coe, Bradley P, Li, Jin, Mohebnasab, Maede, Chang, Xiao, Connolly, John, Kao, Charlly, Wei, Zhi, Bradfield, Jonathan, Kim, Cecilia, Hou, Cuiping, Khan, Munir, Mentch, Frank, Qiu, Haijun, Bakay, Marina, Cardinale, Christopher, Lemma, Maria, Abrams, Debra, Bridglall-Jhingoor, Andrew, Behr, Meckenzie, Harrison, Shanell, Otieno, George, Thomas, Alexandria, Wang, Fengxiang, Chiavacci, Rosetta, Wu, Lawrence, Hadley, Dexter, Goldmuntz, Elizabeth, Elia, Josephine, Maris, John, Grundmeier, Robert, Devoto, Marcella, Keating, Brendan, March, Michael, Pellagrino, Renata, Grant, Struan FA, Sleiman, Patrick MA, Li, Mingyao, Eichler, Evan E, Hakonarson, Hakon, Li, Yun Rose, Glessner, Joseph T, Coe, Bradley P, Li, Jin, Mohebnasab, Maede, Chang, Xiao, Connolly, John, Kao, Charlly, Wei, Zhi, Bradfield, Jonathan, Kim, Cecilia, Hou, Cuiping, Khan, Munir, Mentch, Frank, Qiu, Haijun, Bakay, Marina, Cardinale, Christopher, Lemma, Maria, Abrams, Debra, Bridglall-Jhingoor, Andrew, Behr, Meckenzie, Harrison, Shanell, Otieno, George, Thomas, Alexandria, Wang, Fengxiang, Chiavacci, Rosetta, Wu, Lawrence, Hadley, Dexter, Goldmuntz, Elizabeth, Elia, Josephine, Maris, John, Grundmeier, Robert, Devoto, Marcella, Keating, Brendan, March, Michael, Pellagrino, Renata, Grant, Struan FA, Sleiman, Patrick MA, Li, Mingyao, Eichler, Evan E, and Hakonarson, Hakon
Abstract: Copy number variants (CNVs) are suggested to have a widespread impact on the human genome and phenotypes. To understand the role of CNVs across human diseases, we examine the CNV genomic landscape of 100,028 unrelated individuals of European ancestry, using SNP and CGH array datasets. We observe an average CNV burden of ~650 kb, identifying a total of 11,314 deletion, 5625 duplication, and 2746 homozygous deletion CNV regions (CNVRs). In all, 13.7% are unreported, 58.6% overlap with at least one gene, and 32.8% interrupt coding exons. These CNVRs are significantly more likely to overlap OMIM genes (2.94-fold), GWAS loci (1.52-fold), and non-coding RNAs (1.44-fold), compared with random distribution (P < 1 × 10-3). We uncover CNV associations with four major disease categories, including autoimmune, cardio-metabolic, oncologic, and neurological/psychiatric diseases, and identify several drug-repurposing opportunities. Our results demonstrate robust frequency definition for large-scale rare variant association studies, identify CNVs associated with major disease categories, and illustrate the pleiotropic impact of CNVs in human disease.
Published: 2019

10. Increased frequency of de novo copy number variants in congenital heart disease by integrative analysis of single nucleotide polymorphism array and exome sequence data.

Author: Glessner, Joseph T, Glessner, Joseph T, Bick, Alexander G, Ito, Kaoru, Homsy, Jason, Rodriguez-Murillo, Laura, Fromer, Menachem, Mazaika, Erica, Vardarajan, Badri, Italia, Michael, Leipzig, Jeremy, DePalma, Steven R, Golhar, Ryan, Sanders, Stephan J, Yamrom, Boris, Ronemus, Michael, Iossifov, Ivan, Willsey, A Jeremy, State, Matthew W, Kaltman, Jonathan R, White, Peter S, Shen, Yufeng, Warburton, Dorothy, Brueckner, Martina, Seidman, Christine, Goldmuntz, Elizabeth, Gelb, Bruce D, Lifton, Richard, Seidman, Jonathan, Hakonarson, Hakon, Chung, Wendy K, Glessner, Joseph T, Glessner, Joseph T, Bick, Alexander G, Ito, Kaoru, Homsy, Jason, Rodriguez-Murillo, Laura, Fromer, Menachem, Mazaika, Erica, Vardarajan, Badri, Italia, Michael, Leipzig, Jeremy, DePalma, Steven R, Golhar, Ryan, Sanders, Stephan J, Yamrom, Boris, Ronemus, Michael, Iossifov, Ivan, Willsey, A Jeremy, State, Matthew W, Kaltman, Jonathan R, White, Peter S, Shen, Yufeng, Warburton, Dorothy, Brueckner, Martina, Seidman, Christine, Goldmuntz, Elizabeth, Gelb, Bruce D, Lifton, Richard, Seidman, Jonathan, Hakonarson, Hakon, and Chung, Wendy K
Abstract: RationaleCongenital heart disease (CHD) is among the most common birth defects. Most cases are of unknown pathogenesis.ObjectiveTo determine the contribution of de novo copy number variants (CNVs) in the pathogenesis of sporadic CHD.Methods and resultsWe studied 538 CHD trios using genome-wide dense single nucleotide polymorphism arrays and whole exome sequencing. Results were experimentally validated using digital droplet polymerase chain reaction. We compared validated CNVs in CHD cases with CNVs in 1301 healthy control trios. The 2 complementary high-resolution technologies identified 63 validated de novo CNVs in 51 CHD cases. A significant increase in CNV burden was observed when comparing CHD trios with healthy trios, using either single nucleotide polymorphism array (P=7×10(-5); odds ratio, 4.6) or whole exome sequencing data (P=6×10(-4); odds ratio, 3.5) and remained after removing 16% of de novo CNV loci previously reported as pathogenic (P=0.02; odds ratio, 2.7). We observed recurrent de novo CNVs on 15q11.2 encompassing CYFIP1, NIPA1, and NIPA2 and single de novo CNVs encompassing DUSP1, JUN, JUP, MED15, MED9, PTPRE SREBF1, TOP2A, and ZEB2, genes that interact with established CHD proteins NKX2-5 and GATA4. Integrating de novo variants in whole exome sequencing and CNV data suggests that ETS1 is the pathogenic gene altered by 11q24.2-q25 deletions in Jacobsen syndrome and that CTBP2 is the pathogenic gene in 10q subtelomeric deletions.ConclusionsWe demonstrate a significantly increased frequency of rare de novo CNVs in CHD patients compared with healthy controls and suggest several novel genetic loci for CHD.
Published: 2014

11. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome

Author: Collins, Ryan L, Brand, Harrison, Redin, Claire E., Hanscom, Carrie, Antolik, Caroline, Stone, Matthew R, Glessner, Joseph T., Mason, Tamara, Pregno, Giulia, Dorrani, Naghmeh, Mandrile, Giorgia, Giachino, Daniela, Perrin, Danielle, Walsh, Cole, Cipicchio, Michelle, Costello, Maura, Stortchevoi, Alexei, An, Joon Yong, Currall, Benjamin B, Seabra, Catarina M, Ragavendran, Ashok, Margolin, Lauren, Martinez-Agosto, Julian A., Lucente, Diane, Levy, Brynn, Sanders, Jan-Stephan, Wapner, Ronald J., Quintero-Rivera, Fabiola, Kloosterman, Wigard, Talkowski, Michael E., Collins, Ryan L, Brand, Harrison, Redin, Claire E., Hanscom, Carrie, Antolik, Caroline, Stone, Matthew R, Glessner, Joseph T., Mason, Tamara, Pregno, Giulia, Dorrani, Naghmeh, Mandrile, Giorgia, Giachino, Daniela, Perrin, Danielle, Walsh, Cole, Cipicchio, Michelle, Costello, Maura, Stortchevoi, Alexei, An, Joon Yong, Currall, Benjamin B, Seabra, Catarina M, Ragavendran, Ashok, Margolin, Lauren, Martinez-Agosto, Julian A., Lucente, Diane, Levy, Brynn, Sanders, Jan-Stephan, Wapner, Ronald J., Quintero-Rivera, Fabiola, Kloosterman, Wigard, and Talkowski, Michael E.
Published: 2017

12. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome

Author: Collins, Ryan L, Brand, Harrison, Redin, Claire E., Hanscom, Carrie, Antolik, Caroline, Stone, Matthew R, Glessner, Joseph T., Mason, Tamara, Pregno, Giulia, Dorrani, Naghmeh, Mandrile, Giorgia, Giachino, Daniela, Perrin, Danielle, Walsh, Cole, Cipicchio, Michelle, Costello, Maura, Stortchevoi, Alexei, An, Joon Yong, Currall, Benjamin B, Seabra, Catarina M, Ragavendran, Ashok, Margolin, Lauren, Martinez-Agosto, Julian A., Lucente, Diane, Levy, Brynn, Sanders, Jan-Stephan, Wapner, Ronald J., Quintero-Rivera, Fabiola, Kloosterman, Wigard, Talkowski, Michael E., Collins, Ryan L, Brand, Harrison, Redin, Claire E., Hanscom, Carrie, Antolik, Caroline, Stone, Matthew R, Glessner, Joseph T., Mason, Tamara, Pregno, Giulia, Dorrani, Naghmeh, Mandrile, Giorgia, Giachino, Daniela, Perrin, Danielle, Walsh, Cole, Cipicchio, Michelle, Costello, Maura, Stortchevoi, Alexei, An, Joon Yong, Currall, Benjamin B, Seabra, Catarina M, Ragavendran, Ashok, Margolin, Lauren, Martinez-Agosto, Julian A., Lucente, Diane, Levy, Brynn, Sanders, Jan-Stephan, Wapner, Ronald J., Quintero-Rivera, Fabiola, Kloosterman, Wigard, and Talkowski, Michael E.
Published: 2017

13. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author: Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E
Published: 2017

14. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome

Author: Collins, Ryan L, Brand, Harrison, Redin, Claire E., Hanscom, Carrie, Antolik, Caroline, Stone, Matthew R, Glessner, Joseph T., Mason, Tamara, Pregno, Giulia, Dorrani, Naghmeh, Mandrile, Giorgia, Giachino, Daniela, Perrin, Danielle, Walsh, Cole, Cipicchio, Michelle, Costello, Maura, Stortchevoi, Alexei, An, Joon Yong, Currall, Benjamin B, Seabra, Catarina M, Ragavendran, Ashok, Margolin, Lauren, Martinez-Agosto, Julian A., Lucente, Diane, Levy, Brynn, Sanders, Jan-Stephan, Wapner, Ronald J., Quintero-Rivera, Fabiola, Kloosterman, Wigard, Talkowski, Michael E., Collins, Ryan L, Brand, Harrison, Redin, Claire E., Hanscom, Carrie, Antolik, Caroline, Stone, Matthew R, Glessner, Joseph T., Mason, Tamara, Pregno, Giulia, Dorrani, Naghmeh, Mandrile, Giorgia, Giachino, Daniela, Perrin, Danielle, Walsh, Cole, Cipicchio, Michelle, Costello, Maura, Stortchevoi, Alexei, An, Joon Yong, Currall, Benjamin B, Seabra, Catarina M, Ragavendran, Ashok, Margolin, Lauren, Martinez-Agosto, Julian A., Lucente, Diane, Levy, Brynn, Sanders, Jan-Stephan, Wapner, Ronald J., Quintero-Rivera, Fabiola, Kloosterman, Wigard, and Talkowski, Michael E.
Published: 2017

15. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author: Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E
Published: 2017

16. Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome

Author: UMC Utrecht, CMM Groep Kloosterman, Child Health, Cancer, Collins, Ryan L, Brand, Harrison, Redin, Claire E., Hanscom, Carrie, Antolik, Caroline, Stone, Matthew R, Glessner, Joseph T., Mason, Tamara, Pregno, Giulia, Dorrani, Naghmeh, Mandrile, Giorgia, Giachino, Daniela, Perrin, Danielle, Walsh, Cole, Cipicchio, Michelle, Costello, Maura, Stortchevoi, Alexei, An, Joon Yong, Currall, Benjamin B, Seabra, Catarina M, Ragavendran, Ashok, Margolin, Lauren, Martinez-Agosto, Julian A., Lucente, Diane, Levy, Brynn, Sanders, Jan-Stephan, Wapner, Ronald J., Quintero-Rivera, Fabiola, Kloosterman, Wigard, Talkowski, Michael E., UMC Utrecht, CMM Groep Kloosterman, Child Health, Cancer, Collins, Ryan L, Brand, Harrison, Redin, Claire E., Hanscom, Carrie, Antolik, Caroline, Stone, Matthew R, Glessner, Joseph T., Mason, Tamara, Pregno, Giulia, Dorrani, Naghmeh, Mandrile, Giorgia, Giachino, Daniela, Perrin, Danielle, Walsh, Cole, Cipicchio, Michelle, Costello, Maura, Stortchevoi, Alexei, An, Joon Yong, Currall, Benjamin B, Seabra, Catarina M, Ragavendran, Ashok, Margolin, Lauren, Martinez-Agosto, Julian A., Lucente, Diane, Levy, Brynn, Sanders, Jan-Stephan, Wapner, Ronald J., Quintero-Rivera, Fabiola, Kloosterman, Wigard, and Talkowski, Michael E.
Published: 2017

17. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author: Genetica Klinische Genetica, Brain, CMM, Circulatory Health, Cancer, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Cuppen, Genetica, CMM Groep Kloosterman, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Genetica Klinische Genetica, Brain, CMM, Circulatory Health, Cancer, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Cuppen, Genetica, CMM Groep Kloosterman, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E
Published: 2017

18. Genetic sharing and heritability of paediatric age of onset autoimmune diseases.

Author: Li, Yun R, Zhao, Sihai D, Li, Jin, Bradfield, Jonathan P, Mohebnasab, Maede, Steel, Laura, Kobie, Julie, Abrams, Debra J, Mentch, Frank D, Glessner, Joseph T, Guo, Yiran, Wei, Zhi, Connolly, John J, Cardinale, Christopher J, Bakay, Marina, Li, Dong, Maggadottir, S Melkorka, Thomas, Kelly A, Qui, Haijun, Chiavacci, Rosetta M, Kim, Cecilia E, Wang, Fengxiang, Snyder, James, Flatø, Berit, Førre, Øystein, Denson, Lee A, Thompson, Susan D, Becker, Mara L, Guthery, Stephen L, Latiano, Anna, Perez, Elena, Resnick, Elena, Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Silverberg, Mark S, Lie, Benedicte A, Punaro, Marilynn, Russell, Richard K, Wilson, David C, Dubinsky, Marla C, Monos, Dimitri S, Annese, Vito, Munro, Jane E, Wise, Carol, Chapel, Helen, Cunningham-Rundles, Charlotte, Orange, Jordan S, Behrens, Edward M, Sullivan, Kathleen E, Kugathasan, Subra, Griffiths, Anne M, Satsangi, Jack, Grant, Struan FA, Sleiman, Patrick MA, Finkel, Terri H, Polychronakos, Constantin, Baldassano, Robert N, Luning Prak, Eline T, Ellis, Justine A, Li, Hongzhe, Keating, Brendan J, Hakonarson, Hakon, Li, Yun R, Zhao, Sihai D, Li, Jin, Bradfield, Jonathan P, Mohebnasab, Maede, Steel, Laura, Kobie, Julie, Abrams, Debra J, Mentch, Frank D, Glessner, Joseph T, Guo, Yiran, Wei, Zhi, Connolly, John J, Cardinale, Christopher J, Bakay, Marina, Li, Dong, Maggadottir, S Melkorka, Thomas, Kelly A, Qui, Haijun, Chiavacci, Rosetta M, Kim, Cecilia E, Wang, Fengxiang, Snyder, James, Flatø, Berit, Førre, Øystein, Denson, Lee A, Thompson, Susan D, Becker, Mara L, Guthery, Stephen L, Latiano, Anna, Perez, Elena, Resnick, Elena, Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Silverberg, Mark S, Lie, Benedicte A, Punaro, Marilynn, Russell, Richard K, Wilson, David C, Dubinsky, Marla C, Monos, Dimitri S, Annese, Vito, Munro, Jane E, Wise, Carol, Chapel, Helen, Cunningham-Rundles, Charlotte, Orange, Jordan S, Behrens, Edward M, Sullivan, Kathleen E, Kugathasan, Subra, Griffiths, Anne M, Satsangi, Jack, Grant, Struan FA, Sleiman, Patrick MA, Finkel, Terri H, Polychronakos, Constantin, Baldassano, Robert N, Luning Prak, Eline T, Ellis, Justine A, Li, Hongzhe, Keating, Brendan J, and Hakonarson, Hakon
Abstract: Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
Published: 2015

19. Genetic sharing and heritability of paediatric age of onset autoimmune diseases.

Author: Li, Yun R, Zhao, Sihai D, Li, Jin, Bradfield, Jonathan P, Mohebnasab, Maede, Steel, Laura, Kobie, Julie, Abrams, Debra J, Mentch, Frank D, Glessner, Joseph T, Guo, Yiran, Wei, Zhi, Connolly, John J, Cardinale, Christopher J, Bakay, Marina, Li, Dong, Maggadottir, S Melkorka, Thomas, Kelly A, Qui, Haijun, Chiavacci, Rosetta M, Kim, Cecilia E, Wang, Fengxiang, Snyder, James, Flatø, Berit, Førre, Øystein, Denson, Lee A, Thompson, Susan D, Becker, Mara L, Guthery, Stephen L, Latiano, Anna, Perez, Elena, Resnick, Elena, Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Silverberg, Mark S, Lie, Benedicte A, Punaro, Marilynn, Russell, Richard K, Wilson, David C, Dubinsky, Marla C, Monos, Dimitri S, Annese, Vito, Munro, Jane E, Wise, Carol, Chapel, Helen, Cunningham-Rundles, Charlotte, Orange, Jordan S, Behrens, Edward M, Sullivan, Kathleen E, Kugathasan, Subra, Griffiths, Anne M, Satsangi, Jack, Grant, Struan FA, Sleiman, Patrick MA, Finkel, Terri H, Polychronakos, Constantin, Baldassano, Robert N, Luning Prak, Eline T, Ellis, Justine A, Li, Hongzhe, Keating, Brendan J, Hakonarson, Hakon, Li, Yun R, Zhao, Sihai D, Li, Jin, Bradfield, Jonathan P, Mohebnasab, Maede, Steel, Laura, Kobie, Julie, Abrams, Debra J, Mentch, Frank D, Glessner, Joseph T, Guo, Yiran, Wei, Zhi, Connolly, John J, Cardinale, Christopher J, Bakay, Marina, Li, Dong, Maggadottir, S Melkorka, Thomas, Kelly A, Qui, Haijun, Chiavacci, Rosetta M, Kim, Cecilia E, Wang, Fengxiang, Snyder, James, Flatø, Berit, Førre, Øystein, Denson, Lee A, Thompson, Susan D, Becker, Mara L, Guthery, Stephen L, Latiano, Anna, Perez, Elena, Resnick, Elena, Strisciuglio, Caterina, Staiano, Annamaria, Miele, Erasmo, Silverberg, Mark S, Lie, Benedicte A, Punaro, Marilynn, Russell, Richard K, Wilson, David C, Dubinsky, Marla C, Monos, Dimitri S, Annese, Vito, Munro, Jane E, Wise, Carol, Chapel, Helen, Cunningham-Rundles, Charlotte, Orange, Jordan S, Behrens, Edward M, Sullivan, Kathleen E, Kugathasan, Subra, Griffiths, Anne M, Satsangi, Jack, Grant, Struan FA, Sleiman, Patrick MA, Finkel, Terri H, Polychronakos, Constantin, Baldassano, Robert N, Luning Prak, Eline T, Ellis, Justine A, Li, Hongzhe, Keating, Brendan J, and Hakonarson, Hakon
Abstract: Autoimmune diseases (AIDs) are polygenic diseases affecting 7-10% of the population in the Western Hemisphere with few effective therapies. Here, we quantify the heritability of paediatric AIDs (pAIDs), including JIA, SLE, CEL, T1D, UC, CD, PS, SPA and CVID, attributable to common genomic variations (SNP-h(2)). SNP-h(2) estimates are most significant for T1D (0.863±s.e. 0.07) and JIA (0.727±s.e. 0.037), more modest for UC (0.386±s.e. 0.04) and CD (0.454±0.025), largely consistent with population estimates and are generally greater than that previously reported by adult GWAS. On pairwise analysis, we observed that the diseases UC-CD (0.69±s.e. 0.07) and JIA-CVID (0.343±s.e. 0.13) are the most strongly correlated. Variations across the MHC strongly contribute to SNP-h(2) in T1D and JIA, but does not significantly contribute to the pairwise rG. Together, our results partition contributions of shared versus disease-specific genomic variations to pAID heritability, identifying pAIDs with unexpected risk sharing, while recapitulating known associations between autoimmune diseases previously reported in adult cohorts.
Published: 2015

20. Biological role and disease impact of copy number variation in complex disease

Author: Glessner, Joseph T and Glessner, Joseph T
Abstract: In the human genome, DNA variants give rise to a variety of complex phenotypes. Ranging from single base mutations to copy number variations (CNVs), many of these variants are neutral in selection and disease etiology, making difficult the detection of true common or rare frequency disease-causing mutations. However, allele frequency comparisons in cases, controls, and families may reveal disease associations. Single nucleotide polymorphism (SNP) arrays and exome sequencing are popular assays for genome-wide variant identification. To limit bias between samples, uniform testing is crucial, including standardized platform versions and sample processing. Bases occupy single points while copy variants occupy segments. Bases are bi-allelic while copies are multi-allelic. One genome also encodes many different cell types. In this study, we investigate how CNV impacts different cell types, including heart, brain and blood cells, all of which serve as models of complex disease. Here, we describe ParseCNV, a systematic algorithm specifically developed as a part of this project to perform more accurate disease associations using SNP arrays or exome sequencing-generated CNV calls with quality tracking of variants, contributing to each significant overlap signal. Red flags of variant quality, genomic region, and overlap profile are assessed in a continuous score and shown to correlate over 90% with independent verification methods. We compared these data with our large internal cohort of 68,000 subjects, with carefully mapped CNVs, which gave a robust rare variant frequency in unaffected populations. In these investigations, we uncovered a number of loci in which CNVs are significantly enriched in non-coding RNA (ncRNA), Online Mendelian Inheritance in Man (OMIM), and genome-wide association study (GWAS) regions, impacting complex disease. By evaluating thoroughly the variant frequencies in pediatric individuals, we subsequently compared these frequencies in geriatric individu
Published: 2014

21. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Author: Casey, Jillian P, Casey, Jillian P, Magalhaes, Tiago, Conroy, Judith M, Regan, Regina, Shah, Naisha, Anney, Richard, Shields, Denis C, Abrahams, Brett S, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Cali, Phil, Correia, Catarina, Corsello, Christina, Coutanche, Marc, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Foley, Suzanne, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Holt, Richard, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Lamb, Janine A, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lord, Catherine, Lund, Sabata C, Maestrini, Elena, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Merikangas, Alison, Miller, Judith, Minopoli, Fiorella, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Nygren, Gudrun, Oliveira, Guiomar, Pagnamenta, Alistair T, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Pickles, Andrew, Pinto, Dalila, Piven, Joseph, Posey, David J, Poustka, Annemarie, Poustka, Fritz, Ragoussis, Jiannis, Roge, Bernadette, Rutter, Michael L, Sequeira, Ana F, Soorya, Latha, Sousa, Inês, Sykes, Nuala, Stoppioni, Vera, Tancredi, Raffaella, Tauber, Maïté, Thompson, Ann P, Thomson, Susanne, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, Jacob AS, Wallace, Simon, Wang, Kai, Wassink, Thomas H, White, Kathy, Casey, Jillian P, Casey, Jillian P, Magalhaes, Tiago, Conroy, Judith M, Regan, Regina, Shah, Naisha, Anney, Richard, Shields, Denis C, Abrahams, Brett S, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Cali, Phil, Correia, Catarina, Corsello, Christina, Coutanche, Marc, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Foley, Suzanne, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Holt, Richard, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Lamb, Janine A, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lord, Catherine, Lund, Sabata C, Maestrini, Elena, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Merikangas, Alison, Miller, Judith, Minopoli, Fiorella, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Nygren, Gudrun, Oliveira, Guiomar, Pagnamenta, Alistair T, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Pickles, Andrew, Pinto, Dalila, Piven, Joseph, Posey, David J, Poustka, Annemarie, Poustka, Fritz, Ragoussis, Jiannis, Roge, Bernadette, Rutter, Michael L, Sequeira, Ana F, Soorya, Latha, Sousa, Inês, Sykes, Nuala, Stoppioni, Vera, Tancredi, Raffaella, Tauber, Maïté, Thompson, Ann P, Thomson, Susanne, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, Jacob AS, Wallace, Simon, Wang, Kai, Wassink, Thomas H, and White, Kathy
Abstract: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Published: 2012

22. Individual common variants exert weak effects on the risk for autism spectrum disorders.

Author: Anney, Richard, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Andrew, Green, Jonathan, Guter, Stephen J, Heron, Elizabeth A, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P, Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Magalhaes, Tiago R, Mantoulan, Carine, McDougle, Christopher J, Melhem, Nadine M, Merikangas, Alison, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J, Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L, Schlitt, Sabine, Shah, Naisha, Sheffield, Val C, Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P, Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Bailey, Anthony J, Anney, Richard, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Andrew, Green, Jonathan, Guter, Stephen J, Heron, Elizabeth A, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P, Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Magalhaes, Tiago R, Mantoulan, Carine, McDougle, Christopher J, Melhem, Nadine M, Merikangas, Alison, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J, Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L, Schlitt, Sabine, Shah, Naisha, Sheffield, Val C, Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P, Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, and Bailey, Anthony J
Abstract: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Published: 2012

23. Individual common variants exert weak effects on the risk for autism spectrum disorders

Author: Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L., Jonge, Maretha de, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Green, Andrew, Green, Jonathan, Guter, Stephen J., Heron, Elizabeth A., Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P., Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Magalhães, Tiago R., Mantoulan, Carine, McDougle, Christopher J., Melhem, Nadine M., Merikangas, Alison, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J., Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Schlitt, Sabine, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Bailey, Anthony J., Battaglia, Agatino, Cantor, Rita M., Coon , Hilary, Cuccaro, Michael L., Dawson, Geraldine, Ennis, Sean, Freitag, Christine M., Geschwind, Daniel H., Haines, Jonathan L., Klauck, Sabine M., McMahon, William M., Maestrini, Elena, Miller, Judith, Monaco, Anthony P., Nelson, Stanley F., Nurnberger, John I., Oliveira, Guiomar, Parr, Jeremy R., Pericak-Vance, Margaret Ann, Piven, Joseph, Schellenberg, Gerard D., Scherer, Stephen W., Vicente, Astrid M., Wassink, Thomas H., Wijsman, Ellen M., Betancur, Catalina, Buxbaum, Joseph D., Cook, Edwin H., Gallagher, Louise, Gill, Michael, Hallmayer, Joachim, Paterson, Andrew D., Sutcliffe, James S., Szatmari, Peter, Vieland, Veronica J., Hakonarson, Hakon, Devlin, Bernie, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L., Jonge, Maretha de, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Green, Andrew, Green, Jonathan, Guter, Stephen J., Heron, Elizabeth A., Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P., Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Magalhães, Tiago R., Mantoulan, Carine, McDougle, Christopher J., Melhem, Nadine M., Merikangas, Alison, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J., Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Schlitt, Sabine, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Bailey, Anthony J., Battaglia, Agatino, Cantor, Rita M., Coon , Hilary, Cuccaro, Michael L., Dawson, Geraldine, Ennis, Sean, Freitag, Christine M., Geschwind, Daniel H., Haines, Jonathan L., Klauck, Sabine M., McMahon, William M., Maestrini, Elena, Miller, Judith, Monaco, Anthony P., Nelson, Stanley F., Nurnberger, John I., Oliveira, Guiomar, Parr, Jeremy R., Pericak-Vance, Margaret Ann, Piven, Joseph, Schellenberg, Gerard D., Scherer, Stephen W., Vicente, Astrid M., Wassink, Thomas H., Wijsman, Ellen M., Betancur, Catalina, Buxbaum, Joseph D., Cook, Edwin H., Gallagher, Louise, Gill, Michael, Hallmayer, Joachim, Paterson, Andrew D., Sutcliffe, James S., Szatmari, Peter, Vieland, Veronica J., Hakonarson, Hakon, and Devlin, Bernie
Abstract: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Published: 2012

24. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder.

Author: Casey, Jillian P, Casey, Jillian P, Magalhaes, Tiago, Conroy, Judith M, Regan, Regina, Shah, Naisha, Anney, Richard, Shields, Denis C, Abrahams, Brett S, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Cali, Phil, Correia, Catarina, Corsello, Christina, Coutanche, Marc, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Foley, Suzanne, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Holt, Richard, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Lamb, Janine A, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lord, Catherine, Lund, Sabata C, Maestrini, Elena, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Merikangas, Alison, Miller, Judith, Minopoli, Fiorella, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Nygren, Gudrun, Oliveira, Guiomar, Pagnamenta, Alistair T, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Pickles, Andrew, Pinto, Dalila, Piven, Joseph, Posey, David J, Poustka, Annemarie, Poustka, Fritz, Ragoussis, Jiannis, Roge, Bernadette, Rutter, Michael L, Sequeira, Ana F, Soorya, Latha, Sousa, Inês, Sykes, Nuala, Stoppioni, Vera, Tancredi, Raffaella, Tauber, Maïté, Thompson, Ann P, Thomson, Susanne, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, Jacob AS, Wallace, Simon, Wang, Kai, Wassink, Thomas H, White, Kathy, Casey, Jillian P, Casey, Jillian P, Magalhaes, Tiago, Conroy, Judith M, Regan, Regina, Shah, Naisha, Anney, Richard, Shields, Denis C, Abrahams, Brett S, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Cali, Phil, Correia, Catarina, Corsello, Christina, Coutanche, Marc, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Foley, Suzanne, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Holt, Richard, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Lamb, Janine A, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lord, Catherine, Lund, Sabata C, Maestrini, Elena, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Merikangas, Alison, Miller, Judith, Minopoli, Fiorella, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Nygren, Gudrun, Oliveira, Guiomar, Pagnamenta, Alistair T, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Pickles, Andrew, Pinto, Dalila, Piven, Joseph, Posey, David J, Poustka, Annemarie, Poustka, Fritz, Ragoussis, Jiannis, Roge, Bernadette, Rutter, Michael L, Sequeira, Ana F, Soorya, Latha, Sousa, Inês, Sykes, Nuala, Stoppioni, Vera, Tancredi, Raffaella, Tauber, Maïté, Thompson, Ann P, Thomson, Susanne, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, Jacob AS, Wallace, Simon, Wang, Kai, Wassink, Thomas H, and White, Kathy
Abstract: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Published: 2012

25. Individual common variants exert weak effects on the risk for autism spectrum disorders.

Author: Anney, Richard, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Andrew, Green, Jonathan, Guter, Stephen J, Heron, Elizabeth A, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P, Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Magalhaes, Tiago R, Mantoulan, Carine, McDougle, Christopher J, Melhem, Nadine M, Merikangas, Alison, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J, Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L, Schlitt, Sabine, Shah, Naisha, Sheffield, Val C, Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P, Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Bailey, Anthony J, Anney, Richard, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L, de Jonge, Maretha, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Green, Andrew, Green, Jonathan, Guter, Stephen J, Heron, Elizabeth A, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P, Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Magalhaes, Tiago R, Mantoulan, Carine, McDougle, Christopher J, Melhem, Nadine M, Merikangas, Alison, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J, Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L, Schlitt, Sabine, Shah, Naisha, Sheffield, Val C, Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P, Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Van Engeland, Herman, Vincent, John B, Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, and Bailey, Anthony J
Abstract: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Published: 2012

26. Individual common variants exert weak effects on the risk for autism spectrum disorders

Author: Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L., Jonge, Maretha de, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Green, Andrew, Green, Jonathan, Guter, Stephen J., Heron, Elizabeth A., Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P., Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Magalhães, Tiago R., Mantoulan, Carine, McDougle, Christopher J., Melhem, Nadine M., Merikangas, Alison, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J., Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Schlitt, Sabine, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Bailey, Anthony J., Battaglia, Agatino, Cantor, Rita M., Coon, Hilary, Cuccaro, Michael L., Dawson, Geraldine, Ennis, Sean, Freitag, Christine M., Geschwind, Daniel H., Haines, Jonathan L., Klauck, Sabine M., McMahon, William M., Maestrini, Elena, Miller, Judith, Monaco, Anthony P., Nelson, Stanley F., Nurnberger, John I., Oliveira, Guiomar, Parr, Jeremy R., Pericak-Vance, Margaret Ann, Piven, Joseph, Schellenberg, Gerard D., Scherer, Stephen W., Vicente, Astrid M., Wassink, Thomas H., Wijsman, Ellen M., Betancur, Catalina, Buxbaum, Joseph D., Cook, Edwin H., Gallagher, Louise, Gill, Michael, Hallmayer, Joachim, Paterson, Andrew D., Sutcliffe, James S., Szatmari, Peter, Vieland, Veronica J., Hakonarson, Hakon, Devlin, Bernie, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Almeida, Joana, Bacchelli, Elena, Baird, Gillian, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Casey, Jillian, Conroy, Judith, Correia, Catarina, Corsello, Christina, Crawford, Emily L., Jonge, Maretha de, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Green, Andrew, Green, Jonathan, Guter, Stephen J., Heron, Elizabeth A., Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Jacob, Suma, Kenny, Graham P., Kim, Cecilia, Kolevzon, Alexander, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Law-Smith, Miriam, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Liu, Xiao-Qing, Lombard, Frances, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Magalhães, Tiago R., Mantoulan, Carine, McDougle, Christopher J., Melhem, Nadine M., Merikangas, Alison, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Noakes, Carolyn, Nygren, Gudrun, Papanikolaou, Katerina, Pagnamenta, Alistair T., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Posey, David J., Poustka, Fritz, Ragoussis, Jiannis, Regan, Regina, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Schlitt, Sabine, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Sykes, Nuala, Tancredi, Raffaella, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Vorstman, JAS, Wallace, Simon, Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Bailey, Anthony J., Battaglia, Agatino, Cantor, Rita M., Coon, Hilary, Cuccaro, Michael L., Dawson, Geraldine, Ennis, Sean, Freitag, Christine M., Geschwind, Daniel H., Haines, Jonathan L., Klauck, Sabine M., McMahon, William M., Maestrini, Elena, Miller, Judith, Monaco, Anthony P., Nelson, Stanley F., Nurnberger, John I., Oliveira, Guiomar, Parr, Jeremy R., Pericak-Vance, Margaret Ann, Piven, Joseph, Schellenberg, Gerard D., Scherer, Stephen W., Vicente, Astrid M., Wassink, Thomas H., Wijsman, Ellen M., Betancur, Catalina, Buxbaum, Joseph D., Cook, Edwin H., Gallagher, Louise, Gill, Michael, Hallmayer, Joachim, Paterson, Andrew D., Sutcliffe, James S., Szatmari, Peter, Vieland, Veronica J., Hakonarson, Hakon, and Devlin, Bernie
Abstract: While it is apparent that rare variation can play an important role in the genetic architecture of autism spectrum disorders (ASDs), the contribution of common variation to the risk of developing ASD is less clear. To produce a more comprehensive picture, we report Stage 2 of the Autism Genome Project genome-wide association study, adding 1301 ASD families and bringing the total to 2705 families analysed (Stages 1 and 2). In addition to evaluating the association of individual single nucleotide polymorphisms (SNPs), we also sought evidence that common variants, en masse, might affect the risk. Despite genotyping over a million SNPs covering the genome, no single SNP shows significant association with ASD or selected phenotypes at a genome-wide level. The SNP that achieves the smallest P-value from secondary analyses is rs1718101. It falls in CNTNAP2, a gene previously implicated in susceptibility for ASD. This SNP also shows modest association with age of word/phrase acquisition in ASD subjects, of interest because features of language development are also associated with other variation in CNTNAP2. In contrast, allele scores derived from the transmission of common alleles to Stage 1 cases significantly predict case status in the independent Stage 2 sample. Despite being significant, the variance explained by these allele scores was small (Vm< 1%). Based on results from individual SNPs and their en masse effect on risk, as inferred from the allele score results, it is reasonable to conclude that common variants affect the risk for ASD but their individual effects are modest.
Published: 2012

27. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Author: Lanktree, Matthew B, Lanktree, Matthew B, Guo, Yiran, Murtaza, Muhammed, Glessner, Joseph T, Bailey, Swneke D, Onland-Moret, N Charlotte, Lettre, Guillaume, Ongen, Halit, Rajagopalan, Ramakrishnan, Johnson, Toby, Shen, Haiqing, Nelson, Christopher P, Klopp, Norman, Baumert, Jens, Padmanabhan, Sandosh, Pankratz, Nathan, Pankow, James S, Shah, Sonia, Taylor, Kira, Barnard, John, Peters, Bas J, Maloney, Cliona M, Lobmeyer, Maximilian T, Stanton, Alice, Zafarmand, M Hadi, Romaine, Simon PR, Mehta, Amar, van Iperen, Erik PA, Gong, Yan, Price, Tom S, Smith, Erin N, Kim, Cecilia E, Li, Yun R, Asselbergs, Folkert W, Atwood, Larry D, Bailey, Kristian M, Bhatt, Deepak, Bauer, Florianne, Behr, Elijah R, Bhangale, Tushar, Boer, Jolanda MA, Boehm, Bernhard O, Bradfield, Jonathan P, Brown, Morris, Braund, Peter S, Burton, Paul R, Carty, Cara, Chandrupatla, Hareesh R, Chen, Wei, Connell, John, Dalgeorgou, Chrysoula, Boer, Anthonius de, Drenos, Fotios, Elbers, Clara C, Fang, James C, Fox, Caroline S, Frackelton, Edward C, Fuchs, Barry, Furlong, Clement E, Gibson, Quince, Gieger, Christian, Goel, Anuj, Grobbee, Diederik E, Hastie, Claire, Howard, Philip J, Huang, Guan-Hua, Johnson, W Craig, Li, Qing, Kleber, Marcus E, Klein, Barbara EK, Klein, Ronald, Kooperberg, Charles, Ky, Bonnie, Lacroix, Andrea, Lanken, Paul, Lathrop, Mark, Li, Mingyao, Marshall, Vanessa, Melander, Olle, Mentch, Frank D, Meyer, Nuala J, Monda, Keri L, Montpetit, Alexandre, Murugesan, Gurunathan, Nakayama, Karen, Nondahl, Dave, Onipinla, Abiodun, Rafelt, Suzanne, Newhouse, Stephen J, Otieno, F George, Patel, Sanjey R, Putt, Mary E, Rodriguez, Santiago, Safa, Radwan N, Sawyer, Douglas B, Schreiner, Pamela J, Simpson, Claire, Sivapalaratnam, Suthesh, Srinivasan, Sathanur R, Suver, Christine, Lanktree, Matthew B, Lanktree, Matthew B, Guo, Yiran, Murtaza, Muhammed, Glessner, Joseph T, Bailey, Swneke D, Onland-Moret, N Charlotte, Lettre, Guillaume, Ongen, Halit, Rajagopalan, Ramakrishnan, Johnson, Toby, Shen, Haiqing, Nelson, Christopher P, Klopp, Norman, Baumert, Jens, Padmanabhan, Sandosh, Pankratz, Nathan, Pankow, James S, Shah, Sonia, Taylor, Kira, Barnard, John, Peters, Bas J, Maloney, Cliona M, Lobmeyer, Maximilian T, Stanton, Alice, Zafarmand, M Hadi, Romaine, Simon PR, Mehta, Amar, van Iperen, Erik PA, Gong, Yan, Price, Tom S, Smith, Erin N, Kim, Cecilia E, Li, Yun R, Asselbergs, Folkert W, Atwood, Larry D, Bailey, Kristian M, Bhatt, Deepak, Bauer, Florianne, Behr, Elijah R, Bhangale, Tushar, Boer, Jolanda MA, Boehm, Bernhard O, Bradfield, Jonathan P, Brown, Morris, Braund, Peter S, Burton, Paul R, Carty, Cara, Chandrupatla, Hareesh R, Chen, Wei, Connell, John, Dalgeorgou, Chrysoula, Boer, Anthonius de, Drenos, Fotios, Elbers, Clara C, Fang, James C, Fox, Caroline S, Frackelton, Edward C, Fuchs, Barry, Furlong, Clement E, Gibson, Quince, Gieger, Christian, Goel, Anuj, Grobbee, Diederik E, Hastie, Claire, Howard, Philip J, Huang, Guan-Hua, Johnson, W Craig, Li, Qing, Kleber, Marcus E, Klein, Barbara EK, Klein, Ronald, Kooperberg, Charles, Ky, Bonnie, Lacroix, Andrea, Lanken, Paul, Lathrop, Mark, Li, Mingyao, Marshall, Vanessa, Melander, Olle, Mentch, Frank D, Meyer, Nuala J, Monda, Keri L, Montpetit, Alexandre, Murugesan, Gurunathan, Nakayama, Karen, Nondahl, Dave, Onipinla, Abiodun, Rafelt, Suzanne, Newhouse, Stephen J, Otieno, F George, Patel, Sanjey R, Putt, Mary E, Rodriguez, Santiago, Safa, Radwan N, Sawyer, Douglas B, Schreiner, Pamela J, Simpson, Claire, Sivapalaratnam, Suthesh, Srinivasan, Sathanur R, and Suver, Christine
Abstract: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
Published: 2011

28. Meta-analysis of Dense Genecentric Association Studies Reveals Common and Uncommon Variants Associated with Height.

Author: Lanktree, Matthew B, Lanktree, Matthew B, Guo, Yiran, Murtaza, Muhammed, Glessner, Joseph T, Bailey, Swneke D, Onland-Moret, N Charlotte, Lettre, Guillaume, Ongen, Halit, Rajagopalan, Ramakrishnan, Johnson, Toby, Shen, Haiqing, Nelson, Christopher P, Klopp, Norman, Baumert, Jens, Padmanabhan, Sandosh, Pankratz, Nathan, Pankow, James S, Shah, Sonia, Taylor, Kira, Barnard, John, Peters, Bas J, Maloney, Cliona M, Lobmeyer, Maximilian T, Stanton, Alice, Zafarmand, M Hadi, Romaine, Simon PR, Mehta, Amar, van Iperen, Erik PA, Gong, Yan, Price, Tom S, Smith, Erin N, Kim, Cecilia E, Li, Yun R, Asselbergs, Folkert W, Atwood, Larry D, Bailey, Kristian M, Bhatt, Deepak, Bauer, Florianne, Behr, Elijah R, Bhangale, Tushar, Boer, Jolanda MA, Boehm, Bernhard O, Bradfield, Jonathan P, Brown, Morris, Braund, Peter S, Burton, Paul R, Carty, Cara, Chandrupatla, Hareesh R, Chen, Wei, Connell, John, Dalgeorgou, Chrysoula, Boer, Anthonius de, Drenos, Fotios, Elbers, Clara C, Fang, James C, Fox, Caroline S, Frackelton, Edward C, Fuchs, Barry, Furlong, Clement E, Gibson, Quince, Gieger, Christian, Goel, Anuj, Grobbee, Diederik E, Hastie, Claire, Howard, Philip J, Huang, Guan-Hua, Johnson, W Craig, Li, Qing, Kleber, Marcus E, Klein, Barbara EK, Klein, Ronald, Kooperberg, Charles, Ky, Bonnie, Lacroix, Andrea, Lanken, Paul, Lathrop, Mark, Li, Mingyao, Marshall, Vanessa, Melander, Olle, Mentch, Frank D, Meyer, Nuala J, Monda, Keri L, Montpetit, Alexandre, Murugesan, Gurunathan, Nakayama, Karen, Nondahl, Dave, Onipinla, Abiodun, Rafelt, Suzanne, Newhouse, Stephen J, Otieno, F George, Patel, Sanjey R, Putt, Mary E, Rodriguez, Santiago, Safa, Radwan N, Sawyer, Douglas B, Schreiner, Pamela J, Simpson, Claire, Sivapalaratnam, Suthesh, Srinivasan, Sathanur R, Suver, Christine, Lanktree, Matthew B, Lanktree, Matthew B, Guo, Yiran, Murtaza, Muhammed, Glessner, Joseph T, Bailey, Swneke D, Onland-Moret, N Charlotte, Lettre, Guillaume, Ongen, Halit, Rajagopalan, Ramakrishnan, Johnson, Toby, Shen, Haiqing, Nelson, Christopher P, Klopp, Norman, Baumert, Jens, Padmanabhan, Sandosh, Pankratz, Nathan, Pankow, James S, Shah, Sonia, Taylor, Kira, Barnard, John, Peters, Bas J, Maloney, Cliona M, Lobmeyer, Maximilian T, Stanton, Alice, Zafarmand, M Hadi, Romaine, Simon PR, Mehta, Amar, van Iperen, Erik PA, Gong, Yan, Price, Tom S, Smith, Erin N, Kim, Cecilia E, Li, Yun R, Asselbergs, Folkert W, Atwood, Larry D, Bailey, Kristian M, Bhatt, Deepak, Bauer, Florianne, Behr, Elijah R, Bhangale, Tushar, Boer, Jolanda MA, Boehm, Bernhard O, Bradfield, Jonathan P, Brown, Morris, Braund, Peter S, Burton, Paul R, Carty, Cara, Chandrupatla, Hareesh R, Chen, Wei, Connell, John, Dalgeorgou, Chrysoula, Boer, Anthonius de, Drenos, Fotios, Elbers, Clara C, Fang, James C, Fox, Caroline S, Frackelton, Edward C, Fuchs, Barry, Furlong, Clement E, Gibson, Quince, Gieger, Christian, Goel, Anuj, Grobbee, Diederik E, Hastie, Claire, Howard, Philip J, Huang, Guan-Hua, Johnson, W Craig, Li, Qing, Kleber, Marcus E, Klein, Barbara EK, Klein, Ronald, Kooperberg, Charles, Ky, Bonnie, Lacroix, Andrea, Lanken, Paul, Lathrop, Mark, Li, Mingyao, Marshall, Vanessa, Melander, Olle, Mentch, Frank D, Meyer, Nuala J, Monda, Keri L, Montpetit, Alexandre, Murugesan, Gurunathan, Nakayama, Karen, Nondahl, Dave, Onipinla, Abiodun, Rafelt, Suzanne, Newhouse, Stephen J, Otieno, F George, Patel, Sanjey R, Putt, Mary E, Rodriguez, Santiago, Safa, Radwan N, Sawyer, Douglas B, Schreiner, Pamela J, Simpson, Claire, Sivapalaratnam, Suthesh, Srinivasan, Sathanur R, and Suver, Christine
Abstract: Height is a classic complex trait with common variants in a growing list of genes known to contribute to the phenotype. Using a genecentric genotyping array targeted toward cardiovascular-related loci, comprising 49,320 SNPs across approximately 2000 loci, we evaluated the association of common and uncommon SNPs with adult height in 114,223 individuals from 47 studies and six ethnicities. A total of 64 loci contained a SNP associated with height at array-wide significance (p < 2.4 × 10(-6)), with 42 loci surpassing the conventional genome-wide significance threshold (p < 5 × 10(-8)). Common variants with minor allele frequencies greater than 5% were observed to be associated with height in 37 previously reported loci. In individuals of European ancestry, uncommon SNPs in IL11 and SMAD3, which would not be genotyped with the use of standard genome-wide genotyping arrays, were strongly associated with height (p < 3 × 10(-11)). Conditional analysis within associated regions revealed five additional variants associated with height independent of lead SNPs within the locus, suggesting allelic heterogeneity. Although underpowered to replicate findings from individuals of European ancestry, the direction of effect of associated variants was largely consistent in African American, South Asian, and Hispanic populations. Overall, we show that dense coverage of genes for uncommon SNPs, coupled with large-scale meta-analysis, can successfully identify additional variants associated with a common complex trait.
Published: 2011

29. A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder

Author: Casey, Jillian P., Magalhães, Tiago R., Conroy, Judith M., Regan, Regina, Shah, Naisha, Anney, Richard, Shields, Denis C., Abrahams, Brett S., Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J., Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Cali, Phil, Correia, Catarina, Corsello, Christina, Coutanche, Marc, Dawson, Geraldine, Jonge, Maretha de, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Foley, Suzanne, Fombonne, Eric, Freitag, Christine M., Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Green, Jonathan, Guter, Stephen J., Hakonarson, Hakon, Holt, Richard, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M., Kolevzon, Alexander, Lamb, Janine A., Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Lord, Catherine, Lund, Sabata C., Maestrini, Elena, Mantoulan, Carine, Marshall, Christian R., McConachie, Helen, McDougle, Christopher J., McGrath, Jane, McMahon, William M., Merikangas, Alison, Miller, Judith, Minopoli, Fiorella, Mirza, Ghazala K., Munson, Jeff, Nelson, Stanley F., Nygren, Gudrun, Oliveira, Guiomar, Pagnamenta, Alistair T., Papanikolaou, Katerina, Parr, Jeremy R., Parrini, Barbara, Pickles, Andrew, Pinto, Dalila, Piven, Joseph, Posey, David J., Poustka, Annemarie, Poustka, Fritz, Ragoussis, Jiannis, Roge, Bernadette, Rutter, Michael L., Sequeira, Ana F., Soorya, Latha, Sousa, Inês, Sykes, Nuala, Stoppioni, Vera, Tancredi, Raffaella, Tauber, Maïté, Thompson, Ann P., Thomson, Susanne, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Vorstman, Jacob A. S., Wallace, Simon, Wang, Kai, Wassink, Thomas H., White, Kathy, Wing, Kirsty, Wittemeyer, Kerstin, Yaspan, Brian L., Zwaigenbaum, Lonnie, Betancur, Catalina, Buxbaum, Joseph D., Cantor, Rita M., Cook, Edwin H., Coon, Hilary, Cuccaro, Michael L., Geschwind, Daniel H., Haines, Jonathan L., Hallmayer, Joachim, Monaco, Anthony P., Nurnberger, John I., Pericak-Vance, Margaret Ann, Schellenberg, Gerard D., Scherer, Stephen W., Sutcliffe, James S., Szatmari, Peter, Vieland, Veronica J., Wijsman, Ellen M., Green, Andrew, Gill, Michael, Gallagher, Louise, Vicente, Astrid M., Ennis, Sean, Casey, Jillian P., Magalhães, Tiago R., Conroy, Judith M., Regan, Regina, Shah, Naisha, Anney, Richard, Shields, Denis C., Abrahams, Brett S., Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J., Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Cali, Phil, Correia, Catarina, Corsello, Christina, Coutanche, Marc, Dawson, Geraldine, Jonge, Maretha de, Delorme, Richard, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Foley, Suzanne, Fombonne, Eric, Freitag, Christine M., Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Green, Jonathan, Guter, Stephen J., Hakonarson, Hakon, Holt, Richard, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M., Kolevzon, Alexander, Lamb, Janine A., Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Lord, Catherine, Lund, Sabata C., Maestrini, Elena, Mantoulan, Carine, Marshall, Christian R., McConachie, Helen, McDougle, Christopher J., McGrath, Jane, McMahon, William M., Merikangas, Alison, Miller, Judith, Minopoli, Fiorella, Mirza, Ghazala K., Munson, Jeff, Nelson, Stanley F., Nygren, Gudrun, Oliveira, Guiomar, Pagnamenta, Alistair T., Papanikolaou, Katerina, Parr, Jeremy R., Parrini, Barbara, Pickles, Andrew, Pinto, Dalila, Piven, Joseph, Posey, David J., Poustka, Annemarie, Poustka, Fritz, Ragoussis, Jiannis, Roge, Bernadette, Rutter, Michael L., Sequeira, Ana F., Soorya, Latha, Sousa, Inês, Sykes, Nuala, Stoppioni, Vera, Tancredi, Raffaella, Tauber, Maïté, Thompson, Ann P., Thomson, Susanne, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Vorstman, Jacob A. S., Wallace, Simon, Wang, Kai, Wassink, Thomas H., White, Kathy, Wing, Kirsty, Wittemeyer, Kerstin, Yaspan, Brian L., Zwaigenbaum, Lonnie, Betancur, Catalina, Buxbaum, Joseph D., Cantor, Rita M., Cook, Edwin H., Coon, Hilary, Cuccaro, Michael L., Geschwind, Daniel H., Haines, Jonathan L., Hallmayer, Joachim, Monaco, Anthony P., Nurnberger, John I., Pericak-Vance, Margaret Ann, Schellenberg, Gerard D., Scherer, Stephen W., Sutcliffe, James S., Szatmari, Peter, Vieland, Veronica J., Wijsman, Ellen M., Green, Andrew, Gill, Michael, Gallagher, Louise, Vicente, Astrid M., and Ennis, Sean
Abstract: Autism spectrum disorder (ASD) is a highly heritable disorder of complex and heterogeneous aetiology. It is primarily characterized by altered cognitive ability including impaired language and communication skills and fundamental deficits in social reciprocity. Despite some notable successes in neuropsychiatric genetics, overall, the high heritability of ASD (~90%) remains poorly explained by common genetic risk variants. However, recent studies suggest that rare genomic variation, in particular copy number variation, may account for a significant proportion of the genetic basis of ASD. We present a large scale analysis to identify candidate genes which may contain low-frequency recessive variation contributing to ASD while taking into account the potential contribution of population differences to the genetic heterogeneity of ASD. Our strategy, homozygous haplotype (HH) mapping, aims to detect homozygous segments of identical haplotype structure that are shared at a higher frequency amongst ASD patients compared to parental controls. The analysis was performed on 1,402 Autism Genome Project trios genotyped for 1 million single nucleotide polymorphisms (SNPs). We identified 25 known and 1,218 novel ASD candidate genes in the discovery analysis including CADM2, ABHD14A, CHRFAM7A, GRIK2, GRM3, EPHA3, FGF10, KCND2, PDZK1, IMMP2L and FOXP2. Furthermore, 10 of the previously reported ASD genes and 300 of the novel candidates identified in the discovery analysis were replicated in an independent sample of 1,182 trios. Our results demonstrate that regions of HH are significantly enriched for previously reported ASD candidate genes and the observed association is independent of gene size (odds ratio 2.10). Our findings highlight the applicability of HH mapping in complex disorders such as ASD and offer an alternative approach to the analysis of genome-wide association data.
Published: 2011

30. A genome-wide scan for common alleles affecting risk for autism.

Author: Anney, Richard, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhaes, Tiago R, Correia, Catarina, Abrahams, Brett S, Sykes, Nuala, Pagnamenta, Alistair T, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R, Casallo, Guillermo, Casey, Jillian, Chu, Su H, Cochrane, Lynne, Corsello, Christina, Crawford, Emily L, Crossett, Andrew, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Heron, Elizabeth A, Hill, Matthew, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lionel, Anath C, Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Melhem, Nadine M, Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J, Poustka, Annemarie, Anney, Richard, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhaes, Tiago R, Correia, Catarina, Abrahams, Brett S, Sykes, Nuala, Pagnamenta, Alistair T, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R, Casallo, Guillermo, Casey, Jillian, Chu, Su H, Cochrane, Lynne, Corsello, Christina, Crawford, Emily L, Crossett, Andrew, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Heron, Elizabeth A, Hill, Matthew, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lionel, Anath C, Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Melhem, Nadine M, Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J, and Poustka, Annemarie
Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Published: 2010

31. A genome-wide scan for common alleles affecting risk for autism

Author: Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhães, Tiago R., Correia, Catarina, Abrahams, Brett S., Sykes, Nuala, Pagnamenta, Alistair T., Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J., Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R., Casallo, Guillermo, Casey, Jillian, Chu, Su H., Cochrane, Lynne, Corsello, Christina, Crawford, Emily L., Crossett, Andrew, Dawson, Geraldine, Jonge, Maretha de, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Freitag, Christine M., Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J., Hakonarson, Hakon, Heron, Elizabeth A., Hill, Matthew, Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M., Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Lionel, Anath C., Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R., McConachie, Helen, McDougle, Christopher J., McGrath, Jane, McMahon, William M., Melhem, Nadine M., Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Nelson, Stanley F., Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J., Poustka, Annemarie, Poustka, Fritz, Prasad, Aparna, Ragoussis, Jiannis, Renshaw, Katy, Rickaby, Jessica, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Bierut, Laura Jean, Rice, John P., Salt, Jeff, Sansom, Katherine, Sato, Daisuke, Segurado, Ricardo, Senman, Lili, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Strawbridge, Christina, Tancredi, Raffaella, Tansey, Katherine, Thiruvahindrapduram, Bhooma, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Wallace, Simon, Wang, Kai, Wang, Zhouzhi, Wassink, Thomas H., Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Yaspan, Brian L., Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Betancur, Catalina, Buxbaum, Joseph D., Cantor, Rita M., Cook, Edwin H., Coon, Hilary, Cuccaro, Michael L., Gallagher, Louise, Geschwind, Daniel H., Gill, Michael, Haines, Jonathan L., Miller, Judith, Monaco, Anthony P., Nurnberger, John I., Paterson, Andrew D., Pericak-Vance, Margaret Ann, Schellenberg, Gerard D., Scherer, Stephen W., Sutcliffe, James S., Szatmari, Peter, Vicente, Astrid M., Vieland, Veronica J., Wijsman, Ellen M., Devlin, Bernie, Ennis, Sean, Hallmayer, Joachim, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhães, Tiago R., Correia, Catarina, Abrahams, Brett S., Sykes, Nuala, Pagnamenta, Alistair T., Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J., Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R., Casallo, Guillermo, Casey, Jillian, Chu, Su H., Cochrane, Lynne, Corsello, Christina, Crawford, Emily L., Crossett, Andrew, Dawson, Geraldine, Jonge, Maretha de, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Freitag, Christine M., Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J., Hakonarson, Hakon, Heron, Elizabeth A., Hill, Matthew, Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M., Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Lionel, Anath C., Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R., McConachie, Helen, McDougle, Christopher J., McGrath, Jane, McMahon, William M., Melhem, Nadine M., Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Nelson, Stanley F., Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J., Poustka, Annemarie, Poustka, Fritz, Prasad, Aparna, Ragoussis, Jiannis, Renshaw, Katy, Rickaby, Jessica, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Bierut, Laura Jean, Rice, John P., Salt, Jeff, Sansom, Katherine, Sato, Daisuke, Segurado, Ricardo, Senman, Lili, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Strawbridge, Christina, Tancredi, Raffaella, Tansey, Katherine, Thiruvahindrapduram, Bhooma, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Wallace, Simon, Wang, Kai, Wang, Zhouzhi, Wassink, Thomas H., Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Yaspan, Brian L., Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Betancur, Catalina, Buxbaum, Joseph D., Cantor, Rita M., Cook, Edwin H., Coon, Hilary, Cuccaro, Michael L., Gallagher, Louise, Geschwind, Daniel H., Gill, Michael, Haines, Jonathan L., Miller, Judith, Monaco, Anthony P., Nurnberger, John I., Paterson, Andrew D., Pericak-Vance, Margaret Ann, Schellenberg, Gerard D., Scherer, Stephen W., Sutcliffe, James S., Szatmari, Peter, Vicente, Astrid M., Vieland, Veronica J., Wijsman, Ellen M., Devlin, Bernie, Ennis, Sean, and Hallmayer, Joachim
Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Published: 2010

32. A genome-wide scan for common alleles affecting risk for autism.

Author: Anney, Richard, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhaes, Tiago R, Correia, Catarina, Abrahams, Brett S, Sykes, Nuala, Pagnamenta, Alistair T, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R, Casallo, Guillermo, Casey, Jillian, Chu, Su H, Cochrane, Lynne, Corsello, Christina, Crawford, Emily L, Crossett, Andrew, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Heron, Elizabeth A, Hill, Matthew, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lionel, Anath C, Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Melhem, Nadine M, Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J, Anney, Richard, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhaes, Tiago R, Correia, Catarina, Abrahams, Brett S, Sykes, Nuala, Pagnamenta, Alistair T, Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J, Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F, Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R, Casallo, Guillermo, Casey, Jillian, Chu, Su H, Cochrane, Lynne, Corsello, Christina, Crawford, Emily L, Crossett, Andrew, Dawson, Geraldine, de Jonge, Maretha, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A, Folstein, Susan E, Fombonne, Eric, Freitag, Christine M, Gilbert, John, Gillberg, Christopher, Glessner, Joseph T, Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J, Hakonarson, Hakon, Heron, Elizabeth A, Hill, Matthew, Holt, Richard, Howe, Jennifer L, Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M, Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M, Lamb, Janine A, Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L, Lionel, Anath C, Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C, Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R, McConachie, Helen, McDougle, Christopher J, McGrath, Jane, McMahon, William M, Melhem, Nadine M, Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J, Mirza, Ghazala K, Munson, Jeff, Nelson, Stanley F, Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R, Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, and Posey, David J
Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10(-8). When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10(-8) threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Published: 2010

33. A genome-wide scan for common alleles affecting risk for autism

Author: Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhães, Tiago R., Correia, Catarina, Abrahams, Brett S., Sykes, Nuala, Pagnamenta, Alistair T., Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J., Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R., Casallo, Guillermo, Casey, Jillian, Chu, Su H., Cochrane, Lynne, Corsello, Christina, Crawford, Emily L., Crossett, Andrew, Dawson, Geraldine, Jonge, Maretha de, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Freitag, Christine M., Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J., Hakonarson, Hakon, Heron, Elizabeth A., Hill, Matthew, Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M., Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Lionel, Anath C., Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R., McConachie, Helen, McDougle, Christopher J., McGrath, Jane, McMahon, William M., Melhem, Nadine M., Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Nelson, Stanley F., Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J., Poustka, Annemarie, Poustka, Fritz, Prasad, Aparna, Ragoussis, Jiannis, Renshaw, Katy, Rickaby, Jessica, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Bierut, Laura Jean, Rice, John P., Salt, Jeff, Sansom, Katherine, Sato, Daisuke, Segurado, Ricardo, Senman, Lili, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Strawbridge, Christina, Tancredi, Raffaella, Tansey, Katherine, Thiruvahindrapduram, Bhooma, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Wallace, Simon, Wang, Kai, Wang, Zhouzhi, Wassink, Thomas H., Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Yaspan, Brian L., Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Betancur, Catalina, Buxbaum, Joseph D., Cantor, Rita M., Cook, Edwin H., Coon, Hilary, Cuccaro, Michael L., Gallagher, Louise, Geschwind, Daniel H., Gill, Michael, Haines, Jonathan L., Miller, Judith, Monaco, Anthony P., Nurnberger, John I., Paterson, Andrew D., Pericak-Vance, Margaret Ann, Schellenberg, Gerard D., Scherer, Stephen W., Sutcliffe, James S., Szatmari, Peter, Vicente, Astrid M., Vieland, Veronica J., Wijsman, Ellen M., Devlin, Bernie, Ennis, Sean, Hallmayer, Joachim, Anney, Richard, Klei, Lambertus, Pinto, Dalila, Regan, Regina, Conroy, Judith, Magalhães, Tiago R., Correia, Catarina, Abrahams, Brett S., Sykes, Nuala, Pagnamenta, Alistair T., Almeida, Joana, Bacchelli, Elena, Bailey, Anthony J., Baird, Gillian, Battaglia, Agatino, Berney, Tom, Bolshakova, Nadia, Bölte, Sven, Bolton, Patrick F., Bourgeron, Thomas, Brennan, Sean, Brian, Jessica, Carson, Andrew R., Casallo, Guillermo, Casey, Jillian, Chu, Su H., Cochrane, Lynne, Corsello, Christina, Crawford, Emily L., Crossett, Andrew, Dawson, Geraldine, Jonge, Maretha de, Delorme, Richard, Drmic, Irene, Duketis, Eftichia, Duque, Frederico, Estes, Annette, Farrar, Penny, Fernandez, Bridget A., Folstein, Susan E., Fombonne, Eric, Freitag, Christine M., Gilbert, John, Gillberg, Christopher, Glessner, Joseph T., Goldberg, Jeremy, Green, Jonathan, Guter, Stephen J., Hakonarson, Hakon, Heron, Elizabeth A., Hill, Matthew, Holt, Richard, Howe, Jennifer L., Hughes, Gillian, Hus, Vanessa, Igliozzi, Roberta, Kim, Cecilia, Klauck, Sabine M., Kolevzon, Alexander, Korvatska, Olena, Kustanovich, Vlad, Lajonchere, Clara M., Lamb, Janine A., Laskawiec, Magdalena, Leboyer, Marion, Le Couteur, Ann, Leventhal, Bennett L., Lionel, Anath C., Liu, Xiao-Qing, Lord, Catherine, Lotspeich, Linda, Lund, Sabata C., Maestrini, Elena, Mahoney, William, Mantoulan, Carine, Marshall, Christian R., McConachie, Helen, McDougle, Christopher J., McGrath, Jane, McMahon, William M., Melhem, Nadine M., Merikangas, Alison, Migita, Ohsuke, Minshew, Nancy J., Mirza, Ghazala K., Munson, Jeff, Nelson, Stanley F., Noakes, Carolyn, Noor, Abdul, Nygren, Gudrun, Oliveira, Guiomar, Papanikolaou, Katerina, Parr, Jeremy R., Parrini, Barbara, Paton, Tara, Pickles, Andrew, Piven, Joseph, Posey, David J., Poustka, Annemarie, Poustka, Fritz, Prasad, Aparna, Ragoussis, Jiannis, Renshaw, Katy, Rickaby, Jessica, Roberts, Wendy, Roeder, Kathryn, Roge, Bernadette, Rutter, Michael L., Bierut, Laura Jean, Rice, John P., Salt, Jeff, Sansom, Katherine, Sato, Daisuke, Segurado, Ricardo, Senman, Lili, Shah, Naisha, Sheffield, Val C., Soorya, Latha, Sousa, Inês, Stoppioni, Vera, Strawbridge, Christina, Tancredi, Raffaella, Tansey, Katherine, Thiruvahindrapduram, Bhooma, Thompson, Ann P., Thomson, Susanne, Tryfon, Ana, Tsiantis, John, Engeland, Herman van, Vincent, John B., Volkmar, Fred, Wallace, Simon, Wang, Kai, Wang, Zhouzhi, Wassink, Thomas H., Wing, Kirsty, Wittemeyer, Kerstin, Wood, Shawn, Yaspan, Brian L., Zurawiecki, Danielle, Zwaigenbaum, Lonnie, Betancur, Catalina, Buxbaum, Joseph D., Cantor, Rita M., Cook, Edwin H., Coon, Hilary, Cuccaro, Michael L., Gallagher, Louise, Geschwind, Daniel H., Gill, Michael, Haines, Jonathan L., Miller, Judith, Monaco, Anthony P., Nurnberger, John I., Paterson, Andrew D., Pericak-Vance, Margaret Ann, Schellenberg, Gerard D., Scherer, Stephen W., Sutcliffe, James S., Szatmari, Peter, Vicente, Astrid M., Vieland, Veronica J., Wijsman, Ellen M., Devlin, Bernie, Ennis, Sean, and Hallmayer, Joachim
Abstract: Although autism spectrum disorders (ASDs) have a substantial genetic basis, most of the known genetic risk has been traced to rare variants, principally copy number variants (CNVs). To identify common risk variation, the Autism Genome Project (AGP) Consortium genotyped 1558 rigorously defined ASD families for 1 million single-nucleotide polymorphisms (SNPs) and analyzed these SNP genotypes for association with ASD. In one of four primary association analyses, the association signal for marker rs4141463, located within MACROD2, crossed the genome-wide association significance threshold of P < 5 × 10−8. When a smaller replication sample was analyzed, the risk allele at rs4141463 was again over-transmitted; yet, consistent with the winner's curse, its effect size in the replication sample was much smaller; and, for the combined samples, the association signal barely fell below the P < 5 × 10−8 threshold. Exploratory analyses of phenotypic subtypes yielded no significant associations after correction for multiple testing. They did, however, yield strong signals within several genes, KIAA0564, PLD5, POU6F2, ST8SIA2 and TAF1C.
Published: 2010

34. Variants of DENND1B associated with asthma in children

Author: Sleiman, Patrick M A, Flory, James, Imielinski, Marcin, Bradfield, Jonathan P, Annaiah, Kiran, Willis-Owen, Saffron A G, Wang, Kai, Rafaels, Nicholas M, Michel, Sven, Bønnelykke, Klaus, Zhang, Haitao, Kim, Cecilia E, Frackelton, Edward C, Glessner, Joseph T, Hou, Cuiping, Otieno, F George, Santa, Erin, Thomas, Kelly, Smith, Ryan M, Glaberson, Wendy R, Garris, Maria, Chiavacci, Rosetta M, Beaty, Terri H, Ruczinski, Ingo, Orange, Jordan M, Allen, Julian, Spergel, Jonathan M, Grundmeier, Robert, Mathias, Rasika A, Christie, Jason D, von Mutius, Erika, Cookson, William O C, Kabesch, Michael, Moffatt, Miriam F, Grunstein, Michael M, Barnes, Kathleen C, Devoto, Marcella, Magnusson, Mark, Li, Hongzhe, Grant, Struan F A, Bisgaard, Hans, Hakonarson, Hakon, Sleiman, Patrick M A, Flory, James, Imielinski, Marcin, Bradfield, Jonathan P, Annaiah, Kiran, Willis-Owen, Saffron A G, Wang, Kai, Rafaels, Nicholas M, Michel, Sven, Bønnelykke, Klaus, Zhang, Haitao, Kim, Cecilia E, Frackelton, Edward C, Glessner, Joseph T, Hou, Cuiping, Otieno, F George, Santa, Erin, Thomas, Kelly, Smith, Ryan M, Glaberson, Wendy R, Garris, Maria, Chiavacci, Rosetta M, Beaty, Terri H, Ruczinski, Ingo, Orange, Jordan M, Allen, Julian, Spergel, Jonathan M, Grundmeier, Robert, Mathias, Rasika A, Christie, Jason D, von Mutius, Erika, Cookson, William O C, Kabesch, Michael, Moffatt, Miriam F, Grunstein, Michael M, Barnes, Kathleen C, Devoto, Marcella, Magnusson, Mark, Li, Hongzhe, Grant, Struan F A, Bisgaard, Hans, and Hakonarson, Hakon
Abstract: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.
Published: 2010

35. Variants of DENND1B associated with asthma in children

Author: Sleiman, Patrick M A, Flory, James, Imielinski, Marcin, Bradfield, Jonathan P, Annaiah, Kiran, Willis-Owen, Saffron A G, Wang, Kai, Rafaels, Nicholas M, Michel, Sven, Bønnelykke, Klaus, Zhang, Haitao, Kim, Cecilia E, Frackelton, Edward C, Glessner, Joseph T, Hou, Cuiping, Otieno, F George, Santa, Erin, Thomas, Kelly, Smith, Ryan M, Glaberson, Wendy R, Garris, Maria, Chiavacci, Rosetta M, Beaty, Terri H, Ruczinski, Ingo, Orange, Jordan M, Allen, Julian, Spergel, Jonathan M, Grundmeier, Robert, Mathias, Rasika A, Christie, Jason D, von Mutius, Erika, Cookson, William O C, Kabesch, Michael, Moffatt, Miriam F, Grunstein, Michael M, Barnes, Kathleen C, Devoto, Marcella, Magnusson, Mark, Li, Hongzhe, Grant, Struan F A, Bisgaard, Hans, Hakonarson, Hakon, Sleiman, Patrick M A, Flory, James, Imielinski, Marcin, Bradfield, Jonathan P, Annaiah, Kiran, Willis-Owen, Saffron A G, Wang, Kai, Rafaels, Nicholas M, Michel, Sven, Bønnelykke, Klaus, Zhang, Haitao, Kim, Cecilia E, Frackelton, Edward C, Glessner, Joseph T, Hou, Cuiping, Otieno, F George, Santa, Erin, Thomas, Kelly, Smith, Ryan M, Glaberson, Wendy R, Garris, Maria, Chiavacci, Rosetta M, Beaty, Terri H, Ruczinski, Ingo, Orange, Jordan M, Allen, Julian, Spergel, Jonathan M, Grundmeier, Robert, Mathias, Rasika A, Christie, Jason D, von Mutius, Erika, Cookson, William O C, Kabesch, Michael, Moffatt, Miriam F, Grunstein, Michael M, Barnes, Kathleen C, Devoto, Marcella, Magnusson, Mark, Li, Hongzhe, Grant, Struan F A, Bisgaard, Hans, and Hakonarson, Hakon
Abstract: Asthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.
Published: 2010

36. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.

Author: Bucan, Maja, Bucan, Maja, Abrahams, Brett S, Wang, Kai, Glessner, Joseph T, Herman, Edward I, Sonnenblick, Lisa I, Alvarez Retuerto, Ana I, Imielinski, Marcin, Hadley, Dexter, Bradfield, Jonathan P, Kim, Cecilia, Gidaya, Nicole B, Lindquist, Ingrid, Hutman, Ted, Sigman, Marian, Kustanovich, Vlad, Lajonchere, Clara M, Singleton, Andrew, Kim, Junhyong, Wassink, Thomas H, McMahon, William M, Owley, Thomas, Sweeney, John A, Coon, Hilary, Nurnberger, John I, Li, Mingyao, Cantor, Rita M, Minshew, Nancy J, Sutcliffe, James S, Cook, Edwin H, Dawson, Geraldine, Buxbaum, Joseph D, Grant, Struan FA, Schellenberg, Gerard D, Geschwind, Daniel H, Hakonarson, Hakon, Bucan, Maja, Bucan, Maja, Abrahams, Brett S, Wang, Kai, Glessner, Joseph T, Herman, Edward I, Sonnenblick, Lisa I, Alvarez Retuerto, Ana I, Imielinski, Marcin, Hadley, Dexter, Bradfield, Jonathan P, Kim, Cecilia, Gidaya, Nicole B, Lindquist, Ingrid, Hutman, Ted, Sigman, Marian, Kustanovich, Vlad, Lajonchere, Clara M, Singleton, Andrew, Kim, Junhyong, Wassink, Thomas H, McMahon, William M, Owley, Thomas, Sweeney, John A, Coon, Hilary, Nurnberger, John I, Li, Mingyao, Cantor, Rita M, Minshew, Nancy J, Sutcliffe, James S, Cook, Edwin H, Dawson, Geraldine, Buxbaum, Joseph D, Grant, Struan FA, Schellenberg, Gerard D, Geschwind, Daniel H, and Hakonarson, Hakon
Abstract: The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
Published: 2009

37. Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.

Author: Bucan, Maja, Gibson, Greg1, Bucan, Maja, Abrahams, Brett S, Wang, Kai, Glessner, Joseph T, Herman, Edward I, Sonnenblick, Lisa I, Alvarez Retuerto, Ana I, Imielinski, Marcin, Hadley, Dexter, Bradfield, Jonathan P, Kim, Cecilia, Gidaya, Nicole B, Lindquist, Ingrid, Hutman, Ted, Sigman, Marian, Kustanovich, Vlad, Lajonchere, Clara M, Singleton, Andrew, Kim, Junhyong, Wassink, Thomas H, McMahon, William M, Owley, Thomas, Sweeney, John A, Coon, Hilary, Nurnberger, John I, Li, Mingyao, Cantor, Rita M, Minshew, Nancy J, Sutcliffe, James S, Cook, Edwin H, Dawson, Geraldine, Buxbaum, Joseph D, Grant, Struan FA, Schellenberg, Gerard D, Geschwind, Daniel H, Hakonarson, Hakon, Bucan, Maja, Gibson, Greg1, Bucan, Maja, Abrahams, Brett S, Wang, Kai, Glessner, Joseph T, Herman, Edward I, Sonnenblick, Lisa I, Alvarez Retuerto, Ana I, Imielinski, Marcin, Hadley, Dexter, Bradfield, Jonathan P, Kim, Cecilia, Gidaya, Nicole B, Lindquist, Ingrid, Hutman, Ted, Sigman, Marian, Kustanovich, Vlad, Lajonchere, Clara M, Singleton, Andrew, Kim, Junhyong, Wassink, Thomas H, McMahon, William M, Owley, Thomas, Sweeney, John A, Coon, Hilary, Nurnberger, John I, Li, Mingyao, Cantor, Rita M, Minshew, Nancy J, Sutcliffe, James S, Cook, Edwin H, Dawson, Geraldine, Buxbaum, Joseph D, Grant, Struan FA, Schellenberg, Gerard D, Geschwind, Daniel H, and Hakonarson, Hakon
Abstract: The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.
Published: 2009

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