Inferring compound heterozygosity from large-scale exome sequencing data

Michael H. Guo; Laurent C. Francioli; Sarah L. Stenton; Julia K. Goodrich; Nicholas A. Watts; Moriel Singer-Berk; Emily Groopman; Philip W. Darnowsky; Matthew Solomonson; Samantha Baxter; Maria Abreu; Carlos A.Aguilar Salinas; Tariq Ahmad; Christine M. Albert; Jessica Alföldi; Diego Ardissino; Irina M. Armean; Gil Atzmon; Eric Banks; John Barnard; Samantha M. Baxter; Laurent Beaugerie; Emelia J. Benjamin; David Benjamin; Louis Bergelson; Michael Boehnke; Lori L. Bonnycastle; Erwin P. Bottinger; Donald W. Bowden; Matthew J. Bown; Steven Brant; Sarah E. Calvo; Hannia Campos; John C. Chambers; Juliana C. Chan; Katherine R. Chao; Sinéad Chapman; Daniel Chasman; Siwei Chen; Rex L. Chisholm; Judy Cho; Rajiv Chowdhury; Mina K. Chung; Wendy K. Chung; Kristian Cibulskis; Bruce Cohen; Ryan L. Collins; Kristen M. Connolly; Adolfo Correa; Miguel Covarrubias; Beryl Cummings; Dana Dabelea; John Danesh; Dawood Darbar; Joshua Denny; Stacey Donnelly; Ravindranath Duggirala; Josée Dupuis; Patrick T. Ellinor; Roberto Elosua; James Emery; Eleina England; Jeanette Erdmann; Tõnu Esko; Emily Evangelista; Yossi Farjoun; Diane Fatkin; Steven Ferriera; Jose Florez; Andre Franke; Martti Färkkilä; Stacey Gabriel; Kiran Garimella; Laura D. Gauthier; Jeff Gentry; Gad Getz; David C. Glahn; Benjamin Glaser; Stephen J. Glatt; David Goldstein; Clicerio Gonzalez; Leif Groop; Sanna Gudmundsson; Namrata Gupta; Andrea Haessly; Christopher Haiman; Ira Hall; Craig Hanis; Matthew Harms; Mikko Hiltunen; Matti M. Holi; Christina M. Hultman; Chaim Jalas; Thibault Jeandet; Mikko Kallela; Diane Kaplan; Jaakko Kaprio; Sekar Kathiresan; Eimear Kenny; Bong Jo Kim; Young Jin Kim; George Kirov; Zan Koenig; Jaspal Kooner; Seppo Koskinen; Harlan M. Krumholz; Subra Kugathasan; Soo Heon Kwak; Markku Laakso; Nicole Lake; Trevyn Langsford; Kristen M. Laricchia; Terho Lehtimäki; Monkol Lek; Emily Lipscomb; Christopher Llanwarne; Ruth J.F. Loos; Steven A. Lubitz; Teresa Tusie Luna; Ronald C.W. Ma; Gregory M. Marcus; Jaume Marrugat; Alicia R. Martin; Kari M. Mattila; Steven McCarroll; Mark I. McCarthy; Jacob McCauley; Dermot McGovern; Ruth McPherson; James B. Meigs; Olle Melander; Andres Metspalu; Deborah Meyers; Eric V. Minikel; Braxton D. Mitchell; Vamsi K. Mootha; Ruchi Munshi; Aliya Naheed; Saman Nazarian; Peter M. Nilsson; Sam Novod; Anne H. O’Donnell-Luria; Michael C. O’Donovan; Yukinori Okada; Dost Ongur; Lorena Orozco; Michael J. Owen; Colin Palmer; Nicholette D. Palmer; Aarno Palotie; Kyong Soo Park; Carlos Pato; Nikelle Petrillo; William Phu; Timothy Poterba; Ann E. Pulver; Dan Rader; Nazneen Rahman; Alex Reiner; Anne M. Remes; Dan Rhodes; Stephen Rich; John D. Rioux; Samuli Ripatti; David Roazen; Dan M. Roden; Jerome I. Rotter; Valentin Ruano-Rubio; Nareh Sahakian; Danish Saleheen; Veikko Salomaa; Andrea Saltzman; Nilesh J. Samani; Jeremiah Scharf; Molly Schleicher; Heribert Schunkert; Sebastian Schönherr; Eleanor Seaby; Cotton Seed; Svati H. Shah; Megan Shand; Moore B. Shoemaker; Tai Shyong; Edwin K. Silverman; Pamela Sklar; J. Gustav Smith; Jonathan T. Smith; Hilkka Soininen; Harry Sokol; Rachel G. Son; Jose Soto; Tim Spector; Christine Stevens; Nathan Stitziel; Patrick F. Sullivan; Jaana Suvisaari; E. Shyong Tai; Michael E. Talkowski; Yekaterina Tarasova; Kent D. Taylor; Yik Ying Teo; Kathleen Tibbetts; Charlotte Tolonen; Ming Tsuang; Tiinamaija Tuomi; Dan Turner; Teresa Tusie-Luna; Erkki Vartiainen; Marquis Vawter; Christopher Vittal; Gordon Wade; Arcturus Wang; Qingbo Wang; James S. Ware; Hugh Watkins; Rinse K. Weersma; Ben Weisburd; Maija Wessman; Nicola Whiffin; Michael W. Wilson; James G. Wilson; Ramnik J. Xavier; Mary T. Yohannes; Grace Tiao; Benjamin M. Neale; Joel N. Hirschhorn; Heidi L. Rehm; Mark J. Daly; Anne O’Donnell-Luria; Konrad J. Karczewski; Daniel G. MacArthur; Kaitlin E. Samocha

doi:10.1038/s41588-023-01608-3

Inferring compound heterozygosity from large-scale exome sequencing data

Michael H. Guo, Laurent C. Francioli, Sarah L. Stenton, Julia K. Goodrich, Nicholas A. Watts, Moriel Singer-Berk, Emily Groopman, Philip W. Darnowsky, Matthew Solomonson, Samantha Baxter, Maria Abreu, Carlos A.Aguilar Salinas, Tariq Ahmad, Christine M. Albert, Jessica Alföldi, Diego Ardissino, Irina M. Armean, Gil Atzmon, Eric Banks, John BarnardSamantha M. Baxter, Laurent Beaugerie, Emelia J. Benjamin, David Benjamin, Louis Bergelson, Michael Boehnke, Lori L. Bonnycastle, Erwin P. Bottinger, Donald W. Bowden, Matthew J. Bown, Steven Brant, Sarah E. Calvo, Hannia Campos, John C. Chambers, Juliana C. Chan, Katherine R. Chao, Sinéad Chapman, Daniel Chasman, Siwei Chen, Rex L. Chisholm, Judy Cho, Rajiv Chowdhury, Mina K. Chung, Wendy K. Chung, Kristian Cibulskis, Bruce Cohen, Ryan L. Collins, Kristen M. Connolly, Adolfo Correa, Miguel Covarrubias, Beryl Cummings, Dana Dabelea, John Danesh, Dawood Darbar, Joshua Denny, Stacey Donnelly, Ravindranath Duggirala, Josée Dupuis, Patrick T. Ellinor, Roberto Elosua, James Emery, Eleina England, Jeanette Erdmann, Tõnu Esko, Emily Evangelista, Yossi Farjoun, Diane Fatkin, Steven Ferriera, Jose Florez, Andre Franke, Martti Färkkilä, Stacey Gabriel, Kiran Garimella, Laura D. Gauthier, Jeff Gentry, Gad Getz, David C. Glahn, Benjamin Glaser, Stephen J. Glatt, David Goldstein, Clicerio Gonzalez, Leif Groop, Sanna Gudmundsson, Namrata Gupta, Andrea Haessly, Christopher Haiman, Ira Hall, Craig Hanis, Matthew Harms, Mikko Hiltunen, Matti M. Holi, Christina M. Hultman, Chaim Jalas, Thibault Jeandet, Mikko Kallela, Diane Kaplan, Jaakko Kaprio, Sekar Kathiresan, Eimear Kenny, Bong Jo Kim, Young Jin Kim, George Kirov, Zan Koenig, Jaspal Kooner, Seppo Koskinen, Harlan M. Krumholz, Subra Kugathasan, Soo Heon Kwak, Markku Laakso, Nicole Lake, Trevyn Langsford, Kristen M. Laricchia, Terho Lehtimäki, Monkol Lek, Emily Lipscomb, Christopher Llanwarne, Ruth J.F. Loos, Steven A. Lubitz, Teresa Tusie Luna, Ronald C.W. Ma, Gregory M. Marcus, Jaume Marrugat, Alicia R. Martin, Kari M. Mattila, Steven McCarroll, Mark I. McCarthy, Jacob McCauley, Dermot McGovern, Ruth McPherson, James B. Meigs, Olle Melander, Andres Metspalu, Deborah Meyers, Eric V. Minikel, Braxton D. Mitchell, Vamsi K. Mootha, Ruchi Munshi, Aliya Naheed, Saman Nazarian, Peter M. Nilsson, Sam Novod, Anne H. O’Donnell-Luria, Michael C. O’Donovan, Yukinori Okada, Dost Ongur, Lorena Orozco, Michael J. Owen, Colin Palmer, Nicholette D. Palmer, Aarno Palotie, Kyong Soo Park, Carlos Pato, Nikelle Petrillo, William Phu, Timothy Poterba, Ann E. Pulver, Dan Rader, Nazneen Rahman, Alex Reiner, Anne M. Remes, Dan Rhodes, Stephen Rich, John D. Rioux, Samuli Ripatti, David Roazen, Dan M. Roden, Jerome I. Rotter, Valentin Ruano-Rubio, Nareh Sahakian, Danish Saleheen, Veikko Salomaa, Andrea Saltzman, Nilesh J. Samani, Jeremiah Scharf, Molly Schleicher, Heribert Schunkert, Sebastian Schönherr, Eleanor Seaby, Cotton Seed, Svati H. Shah, Megan Shand, Moore B. Shoemaker, Tai Shyong, Edwin K. Silverman, Pamela Sklar, J. Gustav Smith, Jonathan T. Smith, Hilkka Soininen, Harry Sokol, Rachel G. Son, Jose Soto, Tim Spector, Christine Stevens, Nathan Stitziel, Patrick F. Sullivan, Jaana Suvisaari, E. Shyong Tai, Michael E. Talkowski, Yekaterina Tarasova, Kent D. Taylor, Yik Ying Teo, Kathleen Tibbetts, Charlotte Tolonen, Ming Tsuang, Tiinamaija Tuomi, Dan Turner, Teresa Tusie-Luna, Erkki Vartiainen, Marquis Vawter, Christopher Vittal, Gordon Wade, Arcturus Wang, Qingbo Wang, James S. Ware, Hugh Watkins, Rinse K. Weersma, Ben Weisburd, Maija Wessman, Nicola Whiffin, Michael W. Wilson, James G. Wilson, Ramnik J. Xavier, Mary T. Yohannes, Grace Tiao, Benjamin M. Neale, Joel N. Hirschhorn, Heidi L. Rehm, Mark J. Daly, Anne O’Donnell-Luria, Konrad J. Karczewski, Daniel G. MacArthur, Kaitlin E. Samocha

Department of Human Biology

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

Abstract

Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.

Original language	English
Pages (from-to)	152-161
Number of pages	10
Journal	Nature Genetics
Volume	56
Issue number	1
DOIs	https://doi.org/10.1038/s41588-023-01608-3
State	Published - Jan 2024

Bibliographical note

Publisher Copyright:
© 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

Genetics

Access to Document

10.1038/s41588-023-01608-3

Cite this

Guo, M. H., Francioli, L. C., Stenton, S. L., Goodrich, J. K., Watts, N. A., Singer-Berk, M., Groopman, E., Darnowsky, P. W., Solomonson, M., Baxter, S., Abreu, M., Salinas, C. A. A., Ahmad, T., Albert, C. M., Alföldi, J., Ardissino, D., Armean, I. M., Atzmon, G., Banks, E., ... Samocha, K. E. (2024). Inferring compound heterozygosity from large-scale exome sequencing data. Nature Genetics, 56(1), 152-161. https://doi.org/10.1038/s41588-023-01608-3

@article{7378dc9359d643e0995287852c9bdde8,

title = "Inferring compound heterozygosity from large-scale exome sequencing data",

abstract = "Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.",

author = "Guo, {Michael H.} and Francioli, {Laurent C.} and Stenton, {Sarah L.} and Goodrich, {Julia K.} and Watts, {Nicholas A.} and Moriel Singer-Berk and Emily Groopman and Darnowsky, {Philip W.} and Matthew Solomonson and Samantha Baxter and Maria Abreu and Salinas, {Carlos A.Aguilar} and Tariq Ahmad and Albert, {Christine M.} and Jessica Alf{\"o}ldi and Diego Ardissino and Armean, {Irina M.} and Gil Atzmon and Eric Banks and John Barnard and Baxter, {Samantha M.} and Laurent Beaugerie and Benjamin, {Emelia J.} and David Benjamin and Louis Bergelson and Michael Boehnke and Bonnycastle, {Lori L.} and Bottinger, {Erwin P.} and Bowden, {Donald W.} and Bown, {Matthew J.} and Steven Brant and Calvo, {Sarah E.} and Hannia Campos and Chambers, {John C.} and Chan, {Juliana C.} and Chao, {Katherine R.} and Sin{\'e}ad Chapman and Daniel Chasman and Siwei Chen and Chisholm, {Rex L.} and Judy Cho and Rajiv Chowdhury and Chung, {Mina K.} and Chung, {Wendy K.} and Kristian Cibulskis and Bruce Cohen and Collins, {Ryan L.} and Connolly, {Kristen M.} and Adolfo Correa and Miguel Covarrubias and Beryl Cummings and Dana Dabelea and John Danesh and Dawood Darbar and Joshua Denny and Stacey Donnelly and Ravindranath Duggirala and Jos{\'e}e Dupuis and Ellinor, {Patrick T.} and Roberto Elosua and James Emery and Eleina England and Jeanette Erdmann and T{\~o}nu Esko and Emily Evangelista and Yossi Farjoun and Diane Fatkin and Steven Ferriera and Jose Florez and Andre Franke and Martti F{\"a}rkkil{\"a} and Stacey Gabriel and Kiran Garimella and Gauthier, {Laura D.} and Jeff Gentry and Gad Getz and Glahn, {David C.} and Benjamin Glaser and Glatt, {Stephen J.} and David Goldstein and Clicerio Gonzalez and Leif Groop and Sanna Gudmundsson and Namrata Gupta and Andrea Haessly and Christopher Haiman and Ira Hall and Craig Hanis and Matthew Harms and Mikko Hiltunen and Holi, {Matti M.} and Hultman, {Christina M.} and Chaim Jalas and Thibault Jeandet and Mikko Kallela and Diane Kaplan and Jaakko Kaprio and Sekar Kathiresan and Eimear Kenny and Kim, {Bong Jo} and Kim, {Young Jin} and George Kirov and Zan Koenig and Jaspal Kooner and Seppo Koskinen and Krumholz, {Harlan M.} and Subra Kugathasan and Kwak, {Soo Heon} and Markku Laakso and Nicole Lake and Trevyn Langsford and Laricchia, {Kristen M.} and Terho Lehtim{\"a}ki and Monkol Lek and Emily Lipscomb and Christopher Llanwarne and Loos, {Ruth J.F.} and Lubitz, {Steven A.} and Luna, {Teresa Tusie} and Ma, {Ronald C.W.} and Marcus, {Gregory M.} and Jaume Marrugat and Martin, {Alicia R.} and Mattila, {Kari M.} and Steven McCarroll and McCarthy, {Mark I.} and Jacob McCauley and Dermot McGovern and Ruth McPherson and Meigs, {James B.} and Olle Melander and Andres Metspalu and Deborah Meyers and Minikel, {Eric V.} and Mitchell, {Braxton D.} and Mootha, {Vamsi K.} and Ruchi Munshi and Aliya Naheed and Saman Nazarian and Nilsson, {Peter M.} and Sam Novod and O{\textquoteright}Donnell-Luria, {Anne H.} and O{\textquoteright}Donovan, {Michael C.} and Yukinori Okada and Dost Ongur and Lorena Orozco and Owen, {Michael J.} and Colin Palmer and Palmer, {Nicholette D.} and Aarno Palotie and Park, {Kyong Soo} and Carlos Pato and Nikelle Petrillo and William Phu and Timothy Poterba and Pulver, {Ann E.} and Dan Rader and Nazneen Rahman and Alex Reiner and Remes, {Anne M.} and Dan Rhodes and Stephen Rich and Rioux, {John D.} and Samuli Ripatti and David Roazen and Roden, {Dan M.} and Rotter, {Jerome I.} and Valentin Ruano-Rubio and Nareh Sahakian and Danish Saleheen and Veikko Salomaa and Andrea Saltzman and Samani, {Nilesh J.} and Jeremiah Scharf and Molly Schleicher and Heribert Schunkert and Sebastian Sch{\"o}nherr and Eleanor Seaby and Cotton Seed and Shah, {Svati H.} and Megan Shand and Shoemaker, {Moore B.} and Tai Shyong and Silverman, {Edwin K.} and Pamela Sklar and Smith, {J. Gustav} and Smith, {Jonathan T.} and Hilkka Soininen and Harry Sokol and Son, {Rachel G.} and Jose Soto and Tim Spector and Christine Stevens and Nathan Stitziel and Sullivan, {Patrick F.} and Jaana Suvisaari and Tai, {E. Shyong} and Talkowski, {Michael E.} and Yekaterina Tarasova and Taylor, {Kent D.} and Teo, {Yik Ying} and Kathleen Tibbetts and Charlotte Tolonen and Ming Tsuang and Tiinamaija Tuomi and Dan Turner and Teresa Tusie-Luna and Erkki Vartiainen and Marquis Vawter and Christopher Vittal and Gordon Wade and Arcturus Wang and Qingbo Wang and Ware, {James S.} and Hugh Watkins and Weersma, {Rinse K.} and Ben Weisburd and Maija Wessman and Nicola Whiffin and Wilson, {Michael W.} and Wilson, {James G.} and Xavier, {Ramnik J.} and Yohannes, {Mary T.} and Grace Tiao and Neale, {Benjamin M.} and Hirschhorn, {Joel N.} and Rehm, {Heidi L.} and Daly, {Mark J.} and Anne O{\textquoteright}Donnell-Luria and Karczewski, {Konrad J.} and MacArthur, {Daniel G.} and Samocha, {Kaitlin E.}",

note = "Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2024",

month = jan,

doi = "10.1038/s41588-023-01608-3",

language = "English",

volume = "56",

pages = "152--161",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

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Guo, MH, Francioli, LC, Stenton, SL, Goodrich, JK, Watts, NA, Singer-Berk, M, Groopman, E, Darnowsky, PW, Solomonson, M, Baxter, S, Abreu, M, Salinas, CAA, Ahmad, T, Albert, CM, Alföldi, J, Ardissino, D, Armean, IM, Atzmon, G, Banks, E, Barnard, J, Baxter, SM, Beaugerie, L, Benjamin, EJ, Benjamin, D, Bergelson, L, Boehnke, M, Bonnycastle, LL, Bottinger, EP, Bowden, DW, Bown, MJ, Brant, S, Calvo, SE, Campos, H, Chambers, JC, Chan, JC, Chao, KR, Chapman, S, Chasman, D, Chen, S, Chisholm, RL, Cho, J, Chowdhury, R, Chung, MK, Chung, WK, Cibulskis, K, Cohen, B, Collins, RL, Connolly, KM, Correa, A, Covarrubias, M, Cummings, B, Dabelea, D, Danesh, J, Darbar, D, Denny, J, Donnelly, S, Duggirala, R, Dupuis, J, Ellinor, PT, Elosua, R, Emery, J, England, E, Erdmann, J, Esko, T, Evangelista, E, Farjoun, Y, Fatkin, D, Ferriera, S, Florez, J, Franke, A, Färkkilä, M, Gabriel, S, Garimella, K, Gauthier, LD, Gentry, J, Getz, G, Glahn, DC, Glaser, B, Glatt, SJ, Goldstein, D, Gonzalez, C, Groop, L, Gudmundsson, S, Gupta, N, Haessly, A, Haiman, C, Hall, I, Hanis, C, Harms, M, Hiltunen, M, Holi, MM, Hultman, CM, Jalas, C, Jeandet, T, Kallela, M, Kaplan, D, Kaprio, J, Kathiresan, S, Kenny, E, Kim, BJ, Kim, YJ, Kirov, G, Koenig, Z, Kooner, J, Koskinen, S, Krumholz, HM, Kugathasan, S, Kwak, SH, Laakso, M, Lake, N, Langsford, T, Laricchia, KM, Lehtimäki, T, Lek, M, Lipscomb, E, Llanwarne, C, Loos, RJF, Lubitz, SA, Luna, TT, Ma, RCW, Marcus, GM, Marrugat, J, Martin, AR, Mattila, KM, McCarroll, S, McCarthy, MI, McCauley, J, McGovern, D, McPherson, R, Meigs, JB, Melander, O, Metspalu, A, Meyers, D, Minikel, EV, Mitchell, BD, Mootha, VK, Munshi, R, Naheed, A, Nazarian, S, Nilsson, PM, Novod, S, O’Donnell-Luria, AH, O’Donovan, MC, Okada, Y, Ongur, D, Orozco, L, Owen, MJ, Palmer, C, Palmer, ND, Palotie, A, Park, KS, Pato, C, Petrillo, N, Phu, W, Poterba, T, Pulver, AE, Rader, D, Rahman, N, Reiner, A, Remes, AM, Rhodes, D, Rich, S, Rioux, JD, Ripatti, S, Roazen, D, Roden, DM, Rotter, JI, Ruano-Rubio, V, Sahakian, N, Saleheen, D, Salomaa, V, Saltzman, A, Samani, NJ, Scharf, J, Schleicher, M, Schunkert, H, Schönherr, S, Seaby, E, Seed, C, Shah, SH, Shand, M, Shoemaker, MB, Shyong, T, Silverman, EK, Sklar, P, Smith, JG, Smith, JT, Soininen, H, Sokol, H, Son, RG, Soto, J, Spector, T, Stevens, C, Stitziel, N, Sullivan, PF, Suvisaari, J, Tai, ES, Talkowski, ME, Tarasova, Y, Taylor, KD, Teo, YY, Tibbetts, K, Tolonen, C, Tsuang, M, Tuomi, T, Turner, D, Tusie-Luna, T, Vartiainen, E, Vawter, M, Vittal, C, Wade, G, Wang, A, Wang, Q, Ware, JS, Watkins, H, Weersma, RK, Weisburd, B, Wessman, M, Whiffin, N, Wilson, MW, Wilson, JG, Xavier, RJ, Yohannes, MT, Tiao, G, Neale, BM, Hirschhorn, JN, Rehm, HL, Daly, MJ, O’Donnell-Luria, A, Karczewski, KJ, MacArthur, DG & Samocha, KE 2024, 'Inferring compound heterozygosity from large-scale exome sequencing data', Nature Genetics, vol. 56, no. 1, pp. 152-161. https://doi.org/10.1038/s41588-023-01608-3

TY - JOUR

T1 - Inferring compound heterozygosity from large-scale exome sequencing data

AU - Guo, Michael H.

AU - Francioli, Laurent C.

AU - Stenton, Sarah L.

AU - Goodrich, Julia K.

AU - Watts, Nicholas A.

AU - Singer-Berk, Moriel

AU - Groopman, Emily

AU - Darnowsky, Philip W.

AU - Solomonson, Matthew

AU - Baxter, Samantha

AU - Abreu, Maria

AU - Salinas, Carlos A.Aguilar

AU - Ahmad, Tariq

AU - Albert, Christine M.

AU - Alföldi, Jessica

AU - Ardissino, Diego

AU - Armean, Irina M.

AU - Atzmon, Gil

AU - Banks, Eric

AU - Barnard, John

AU - Baxter, Samantha M.

AU - Beaugerie, Laurent

AU - Benjamin, Emelia J.

AU - Benjamin, David

AU - Bergelson, Louis

AU - Boehnke, Michael

AU - Bonnycastle, Lori L.

AU - Bottinger, Erwin P.

AU - Bowden, Donald W.

AU - Bown, Matthew J.

AU - Brant, Steven

AU - Calvo, Sarah E.

AU - Campos, Hannia

AU - Chambers, John C.

AU - Chan, Juliana C.

AU - Chao, Katherine R.

AU - Chapman, Sinéad

AU - Chasman, Daniel

AU - Chen, Siwei

AU - Chisholm, Rex L.

AU - Cho, Judy

AU - Chowdhury, Rajiv

AU - Chung, Mina K.

AU - Chung, Wendy K.

AU - Cibulskis, Kristian

AU - Cohen, Bruce

AU - Collins, Ryan L.

AU - Connolly, Kristen M.

AU - Correa, Adolfo

AU - Covarrubias, Miguel

AU - Cummings, Beryl

AU - Dabelea, Dana

AU - Danesh, John

AU - Darbar, Dawood

AU - Denny, Joshua

AU - Donnelly, Stacey

AU - Duggirala, Ravindranath

AU - Dupuis, Josée

AU - Ellinor, Patrick T.

AU - Elosua, Roberto

AU - Emery, James

AU - England, Eleina

AU - Erdmann, Jeanette

AU - Esko, Tõnu

AU - Evangelista, Emily

AU - Farjoun, Yossi

AU - Fatkin, Diane

AU - Ferriera, Steven

AU - Florez, Jose

AU - Franke, Andre

AU - Färkkilä, Martti

AU - Gabriel, Stacey

AU - Garimella, Kiran

AU - Gauthier, Laura D.

AU - Gentry, Jeff

AU - Getz, Gad

AU - Glahn, David C.

AU - Glaser, Benjamin

AU - Glatt, Stephen J.

AU - Goldstein, David

AU - Gonzalez, Clicerio

AU - Groop, Leif

AU - Gudmundsson, Sanna

AU - Gupta, Namrata

AU - Haessly, Andrea

AU - Haiman, Christopher

AU - Hall, Ira

AU - Hanis, Craig

AU - Harms, Matthew

AU - Hiltunen, Mikko

AU - Holi, Matti M.

AU - Hultman, Christina M.

AU - Jalas, Chaim

AU - Jeandet, Thibault

AU - Kallela, Mikko

AU - Kaplan, Diane

AU - Kaprio, Jaakko

AU - Kathiresan, Sekar

AU - Kenny, Eimear

AU - Kim, Bong Jo

AU - Kim, Young Jin

AU - Kirov, George

AU - Koenig, Zan

AU - Kooner, Jaspal

AU - Koskinen, Seppo

AU - Krumholz, Harlan M.

AU - Kugathasan, Subra

AU - Kwak, Soo Heon

AU - Laakso, Markku

AU - Lake, Nicole

AU - Langsford, Trevyn

AU - Laricchia, Kristen M.

AU - Lehtimäki, Terho

AU - Lek, Monkol

AU - Lipscomb, Emily

AU - Llanwarne, Christopher

AU - Loos, Ruth J.F.

AU - Lubitz, Steven A.

AU - Luna, Teresa Tusie

AU - Ma, Ronald C.W.

AU - Marcus, Gregory M.

AU - Marrugat, Jaume

AU - Martin, Alicia R.

AU - Mattila, Kari M.

AU - McCarroll, Steven

AU - McCarthy, Mark I.

AU - McCauley, Jacob

AU - McGovern, Dermot

AU - McPherson, Ruth

AU - Meigs, James B.

AU - Melander, Olle

AU - Metspalu, Andres

AU - Meyers, Deborah

AU - Minikel, Eric V.

AU - Mitchell, Braxton D.

AU - Mootha, Vamsi K.

AU - Munshi, Ruchi

AU - Naheed, Aliya

AU - Nazarian, Saman

AU - Nilsson, Peter M.

AU - Novod, Sam

AU - O’Donnell-Luria, Anne H.

AU - O’Donovan, Michael C.

AU - Okada, Yukinori

AU - Ongur, Dost

AU - Orozco, Lorena

AU - Owen, Michael J.

AU - Palmer, Colin

AU - Palmer, Nicholette D.

AU - Palotie, Aarno

AU - Park, Kyong Soo

AU - Pato, Carlos

AU - Petrillo, Nikelle

AU - Phu, William

AU - Poterba, Timothy

AU - Pulver, Ann E.

AU - Rader, Dan

AU - Rahman, Nazneen

AU - Reiner, Alex

AU - Remes, Anne M.

AU - Rhodes, Dan

AU - Rich, Stephen

AU - Rioux, John D.

AU - Ripatti, Samuli

AU - Roazen, David

AU - Roden, Dan M.

AU - Rotter, Jerome I.

AU - Ruano-Rubio, Valentin

AU - Sahakian, Nareh

AU - Saleheen, Danish

AU - Salomaa, Veikko

AU - Saltzman, Andrea

AU - Samani, Nilesh J.

AU - Scharf, Jeremiah

AU - Schleicher, Molly

AU - Schunkert, Heribert

AU - Schönherr, Sebastian

AU - Seaby, Eleanor

AU - Seed, Cotton

AU - Shah, Svati H.

AU - Shand, Megan

AU - Shoemaker, Moore B.

AU - Shyong, Tai

AU - Silverman, Edwin K.

AU - Sklar, Pamela

AU - Smith, J. Gustav

AU - Smith, Jonathan T.

AU - Soininen, Hilkka

AU - Sokol, Harry

AU - Son, Rachel G.

AU - Soto, Jose

AU - Spector, Tim

AU - Stevens, Christine

AU - Stitziel, Nathan

AU - Sullivan, Patrick F.

AU - Suvisaari, Jaana

AU - Tai, E. Shyong

AU - Talkowski, Michael E.

AU - Tarasova, Yekaterina

AU - Taylor, Kent D.

AU - Teo, Yik Ying

AU - Tibbetts, Kathleen

AU - Tolonen, Charlotte

AU - Tsuang, Ming

AU - Tuomi, Tiinamaija

AU - Turner, Dan

AU - Tusie-Luna, Teresa

AU - Vartiainen, Erkki

AU - Vawter, Marquis

AU - Vittal, Christopher

AU - Wade, Gordon

AU - Wang, Arcturus

AU - Wang, Qingbo

AU - Ware, James S.

AU - Watkins, Hugh

AU - Weersma, Rinse K.

AU - Weisburd, Ben

AU - Wessman, Maija

AU - Whiffin, Nicola

AU - Wilson, Michael W.

AU - Wilson, James G.

AU - Xavier, Ramnik J.

AU - Yohannes, Mary T.

AU - Tiao, Grace

AU - Neale, Benjamin M.

AU - Hirschhorn, Joel N.

AU - Rehm, Heidi L.

AU - Daly, Mark J.

AU - O’Donnell-Luria, Anne

AU - Karczewski, Konrad J.

AU - MacArthur, Daniel G.

AU - Samocha, Kaitlin E.

PY - 2024/1

Y1 - 2024/1

N2 - Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.

AB - Recessive diseases arise when both copies of a gene are impacted by a damaging genetic variant. When a patient carries two potentially causal variants in a gene, accurate diagnosis requires determining that these variants occur on different copies of the chromosome (that is, are in trans) rather than on the same copy (that is, in cis). However, current approaches for determining phase, beyond parental testing, are limited in clinical settings. Here we developed a strategy for inferring phase for rare variant pairs within genes, leveraging genotypes observed in the Genome Aggregation Database (v2, n = 125,748 exomes). Our approach estimates phase with 96% accuracy, both in trio data and in patients with Mendelian conditions and presumed causal compound heterozygous variants. We provide a public resource of phasing estimates for coding variants and counts per gene of rare variants in trans that can aid interpretation of rare co-occurring variants in the context of recessive disease.

UR - http://www.scopus.com/inward/record.url?scp=85181415190&partnerID=8YFLogxK

U2 - 10.1038/s41588-023-01608-3

DO - 10.1038/s41588-023-01608-3

M3 - Article

C2 - 38057443

AN - SCOPUS:85181415190

SN - 1061-4036

VL - 56

SP - 152

EP - 161

JO - Nature Genetics

JF - Nature Genetics

IS - 1

ER -

Inferring compound heterozygosity from large-scale exome sequencing data

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