Burden of Mendelian disorders in a large Middle Eastern biobank.
Arab population
Biobank
Consanguinity
Genome sequencing
Mendelian disorders
Middle East
Pathogenic variants
Qatar
Rare genetic disease
Journal
Genome medicine
ISSN: 1756-994X
Titre abrégé: Genome Med
Pays: England
ID NLM: 101475844
Informations de publication
Date de publication:
08 Apr 2024
08 Apr 2024
Historique:
received:
01
07
2023
accepted:
19
02
2024
medline:
8
4
2024
pubmed:
8
4
2024
entrez:
7
4
2024
Statut:
epublish
Résumé
Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies. Here, we interrogate 6045 whole genomes from Qatar-a Middle Eastern population with high consanguinity and understudied mutational burden-enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits. We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1-3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region. This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.
Sections du résumé
BACKGROUND
BACKGROUND
Genome sequencing of large biobanks from under-represented ancestries provides a valuable resource for the interrogation of Mendelian disease burden at world population level, complementing small-scale familial studies.
METHODS
METHODS
Here, we interrogate 6045 whole genomes from Qatar-a Middle Eastern population with high consanguinity and understudied mutational burden-enrolled at the national Biobank and phenotyped for 58 clinically-relevant quantitative traits. We examine a curated set of 2648 Mendelian genes from 20 panels, annotating known and novel pathogenic variants and assessing their penetrance and impact on the measured traits.
RESULTS
RESULTS
We find that 62.5% of participants are carriers of at least 1 known pathogenic variant relating to recessive conditions, with homozygosity observed in 1 in 150 subjects (0.6%) for which Peninsular Arabs are particularly enriched versus other ancestries (5.8-fold). On average, 52.3 loss-of-function variants were found per genome, 6.5 of which affect a known Mendelian gene. Several variants annotated in ClinVar/HGMD as pathogenic appeared at intermediate frequencies in this cohort (1-3%), highlighting Arab founder effect, while others have exceedingly high frequencies (> 5%) prompting reconsideration as benign. Furthermore, cumulative gene burden analysis revealed 56 genes having gene carrier frequency > 1/50, including 5 ACMG Tier 3 panel genes which would be candidates for adding to newborn screening in the country. Additionally, leveraging 58 biobank traits, we systematically assess the impact of novel/rare variants on phenotypes and discover 39 candidate large-effect variants associating with extreme quantitative traits. Furthermore, through rare variant burden testing, we discover 13 genes with high mutational load, including 5 with impact on traits relevant to disease conditions, including metabolic disorder and type 2 diabetes, consistent with the high prevalence of these conditions in the region.
CONCLUSIONS
CONCLUSIONS
This study on the first phase of the growing Qatar Genome Program cohort provides a comprehensive resource from a Middle Eastern population to understand the global mutational burden in Mendelian genes and their impact on traits in seemingly healthy individuals in high consanguinity settings.
Identifiants
pubmed: 38584274
doi: 10.1186/s13073-024-01307-6
pii: 10.1186/s13073-024-01307-6
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
46Subventions
Organisme : Qatar National Research Fund
ID : QF-QBB-RES-PUB-003
Investigateurs
Said I Ismail
(SI)
Wadha Al-Muftah
(W)
Radja Badji
(R)
Hamdi Mbarek
(H)
Dima Darwish
(D)
Tasnim Fadl
(T)
Heba Yasin
(H)
Maryem Ennaifar
(M)
Rania Abdellatif
(R)
Fatima Alkuwari
(F)
Muhammad Alvi
(M)
Yasser Al-Sarraj
(Y)
Chadi Saad
(C)
Asmaa Althani
(A)
Eleni Fethnou
(E)
Fatima Qafoud
(F)
Eiman Alkhayat
(E)
Nahla Afifi
(N)
Sara Tomei
(S)
Wei Liu
(W)
Kun Wang
(K)
Stephan Lorenz
(S)
Hakeem Almabrazi
(H)
Fazulur Rehaman Vempalli
(FR)
Ramzi Temanni
(R)
Tariq Abu Saqri
(TA)
Mohammedhusen Khatib
(M)
Mehshad Hamza
(M)
Tariq Abu Zaid
(TA)
Ahmed El Khouly
(AE)
Tushar Pathare
(T)
Shafeeq Poolat
(S)
Rashid Al-Ali
(R)
Omar Albagha
(O)
Souhaila Al-Khodor
(S)
Mashael Alshafai
(M)
Lotfi Chouchane
(L)
Xavier Estivill
(X)
Hamdi Mbarek
(H)
Jithesh V Puthen
(JV)
Karsten Suhre
(K)
Zohreh Tatari
(Z)
Informations de copyright
© 2024. The Author(s).
Références
Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019;179(6):885–92.
pubmed: 30883013
doi: 10.1002/ajmg.a.61124
Fraiman YS, Wojcik MH. The influence of social determinants of health on the genetic diagnostic odyssey: who remains undiagnosed, why, and to what effect? Pediatr Res. 2021;89(2):295–300.
pubmed: 32932427
doi: 10.1038/s41390-020-01151-5
Fakhro KA, Robay A, Rodrigues-Flores JL, Mezey JG, Al-Shakaki AA, Chidiac O, et al. Point of care exome sequencing reveals allelic and phenotypic heterogeneity underlying Mendelian disease in Qatar. Hum Mol Genet. 2019;28(23):3970–81.
pubmed: 31625567
Wright CF, FitzPatrick DR, Firth HV. Paediatric genomics: diagnosing rare disease in children. Nat Rev Genet. 2018;19(5):253–68.
pubmed: 29398702
doi: 10.1038/nrg.2017.116
Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD, et al. The genetic basis of Mendelian phenotypes: discoveries, challenges, and opportunities. Am J Hum Genet. 2015;97(2):199–215.
pubmed: 26166479
pmcid: 4573249
doi: 10.1016/j.ajhg.2015.06.009
Boycott KM, Rath A, Chong JX, Hartley T, Alkuraya FS, Baynam G, et al. International cooperation to enable the diagnosis of all rare genetic diseases. Am J Hum Genet. 2017;100(5):695–705.
pubmed: 28475856
pmcid: 5420351
doi: 10.1016/j.ajhg.2017.04.003
Bainbridge MN, Wiszniewski W, Murdock DR, Friedman J, Gonzaga-Jauregui C, Newsham I, et al. Whole-genome sequencing for optimized patient management. Sci Transl Med. 2011;3(87):87re3.
pubmed: 21677200
pmcid: 3314311
doi: 10.1126/scitranslmed.3002243
Bernarde C, Keravec M, Mounier J, Gouriou S, Rault G, Ferec C, et al. Impact of the CFTR-potentiator ivacaftor on airway microbiota in cystic fibrosis patients carrying a G551D mutation. PLoS One. 2015;10(4):e0124124.
pubmed: 25853698
pmcid: 4390299
doi: 10.1371/journal.pone.0124124
Cavazzana M, Antoniani C, Miccio A. Gene therapy for beta-hemoglobinopathies. Mol Ther. 2017;25(5):1142–54.
pubmed: 28377044
pmcid: 5417842
doi: 10.1016/j.ymthe.2017.03.024
Dever DP, Bak RO, Reinisch A, Camarena J, Washington G, Nicolas CE, et al. CRISPR/Cas9 beta-globin gene targeting in human haematopoietic stem cells. Nature. 2016;539(7629):384–9.
pubmed: 27820943
pmcid: 5898607
doi: 10.1038/nature20134
Schlander M, Holm S, Nord E, Richardson J, Garattini S, Kolominsky-Rabas P, et al. 8th European Conference on Rare Diseases & Orphan Products (ECRD 2016). Orphanet J Rare Dis. 2016;11(Suppl 1):143.
doi: 10.1186/s13023-016-0515-y
Chatzimichali EA, Brent S, Hutton B, Perrett D, Wright CF, Bevan AP, et al. Facilitating collaboration in rare genetic disorders through effective matchmaking in DECIPHER. Hum Mutat. 2015;36(10):941–9.
pubmed: 26220709
pmcid: 4832335
doi: 10.1002/humu.22842
Deciphering Developmental Disorders S. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542(7642):433–8.
doi: 10.1038/nature21062
Sawyer SL, Hartley T, Dyment DA, Beaulieu CL, Schwartzentruber J, Smith A, et al. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet. 2016;89(3):275–84.
pubmed: 26283276
doi: 10.1111/cge.12654
Petrovski S, Goldstein DB. Unequal representation of genetic variation across ancestry groups creates healthcare inequality in the application of precision medicine. Genome Biol. 2016;17(1):157.
pubmed: 27418169
pmcid: 4944427
doi: 10.1186/s13059-016-1016-y
Fakhro KA, Staudt MR, Ramstetter MD, Robay A, Malek JA, Badii R, et al. The Qatar genome: a population-specific tool for precision medicine in the Middle East. Hum Genome Var. 2016;3:16016.
pubmed: 27408750
pmcid: 4927697
doi: 10.1038/hgv.2016.16
Sandridge AL, Takeddin J, Al-Kaabi E, Frances Y. Consanguinity in Qatar: knowledge, attitude and practice in a population born between 1946 and 1991. J Biosoc Sci. 2010;42(1):59–82.
pubmed: 19895726
doi: 10.1017/S002193200999023X
Bener A, Alali KA. Consanguineous marriage in a newly developed country: the Qatari population. J Biosoc Sci. 2006;38(2):239–46.
pubmed: 16490156
doi: 10.1017/S0021932004007060
Scott EM, Halees A, Itan Y, Spencer EG, He Y, Azab MA, et al. Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet. 2016;48(9):1071–6.
pubmed: 27428751
pmcid: 5019950
doi: 10.1038/ng.3592
Ben-Omran T, Al Ghanim K, Yavarna T, El Akoum M, Samara M, Chandra P, et al. Effects of consanguinity in a cohort of subjects with certain genetic disorders in Qatar. Mol Genet Genomic Med. 2020;8(1):e1051.
pubmed: 31793205
doi: 10.1002/mgg3.1051
Fakhro KA, Elbardisi H, Arafa M, Robay A, Rodriguez-Flores JL, Al-Shakaki A, et al. Point-of-care whole-exome sequencing of idiopathic male infertility. Genet Med. 2018;20(11):1365–73.
pubmed: 29790874
doi: 10.1038/gim.2018.10
Razali RM, Rodriguez-Flores J, Ghorbani M, Naeem H, Aamer W, Aliyev E, et al. Thousands of Qatari genomes inform human migration history and improve imputation of Arab haplotypes. Nat Commun. 2021;12(1):5929.
pubmed: 34642339
pmcid: 8511259
doi: 10.1038/s41467-021-25287-y
Rodriguez-Flores JL, Fakhro K, Hackett NR, Salit J, Fuller J, Agosto-Perez F, et al. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Hum Mutat. 2014;35(1):105–16.
pubmed: 24123366
doi: 10.1002/humu.22460
Al-Dewik N, Mohd H, Al-Mureikhi M, Ali R, Al-Mesaifri F, Mahmoud L, et al. Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: The Qatari experience. Am J Med Genet A. 2019;179(6):927–35.
pubmed: 30919572
pmcid: 6916397
doi: 10.1002/ajmg.a.61126
Saleh S, Beyyumi E, Al Kaabi A, Hertecant J, Barakat D, Al Dhaheri NS, et al. Spectrum of neuro-genetic disorders in the United Arab Emirates national population. Clin Genet. 2021;100(5):573–600.
pubmed: 34374989
doi: 10.1111/cge.14044
Alshenaifi J, Ewida N, Anazi S, Shamseldin HE, Patel N, Maddirevula S, et al. The many faces of peroxisomal disorders: lessons from a large Arab cohort. Clin Genet. 2019;95(2):310–9.
pubmed: 30561787
doi: 10.1111/cge.13481
Carress H, Lawson DJ, Elhaik E. Population genetic considerations for using biobanks as international resources in the pandemic era and beyond. BMC Genomics. 2021;22(1):351.
pubmed: 34001009
pmcid: 8127217
doi: 10.1186/s12864-021-07618-x
Mbarek H, Devadoss Gandhi G, Selvaraj S, Al-Muftah W, Badji R, Al-Sarraj Y, et al. Qatar genome: insights on genomics from the Middle East. Hum Mutat. 2022;43(4):499–510.
pubmed: 35112413
doi: 10.1002/humu.24336
Elfatih A, Mifsud B, Syed N, Badii R, Mbarek H, Abbaszadeh F, et al. Actionable genomic variants in 6045 participants from the Qatar Genome Program. Hum Mutat. 2021;42(12):1584–601.
doi: 10.1002/humu.24278
Al Kuwari H, Al Thani A, Al Marri A, Al Kaabi A, Abderrahim H, Afifi N, et al. The Qatar Biobank: background and methods. BMC Public Health. 2015;3(15):1208.
doi: 10.1186/s12889-015-2522-7
Al Thani A, Fthenou E, Paparrodopoulos S, Al Marri A, Shi Z, Qafoud F, et al. Qatar Biobank cohort study: study design and first results. Am J Epidemiol. 2019;188(8):1420–33.
pubmed: 30927351
doi: 10.1093/aje/kwz084
DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet. 2011;43(5):491–8.
pubmed: 21478889
pmcid: 3083463
doi: 10.1038/ng.806
Cingolani P, Platts A, le Wang L, Coon M, Nguyen T, Wang L, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly Austin. 2012;6(2):80–92.
pubmed: 22728672
pmcid: 3679285
Sherry ST, Ward MH, Kholodov M, Baker J, Phan L, Smigielski EM, et al. dbSNP: the NCBI database of genetic variation. Nucleic Acids Res. 2001;29(1):308–11.
pubmed: 11125122
pmcid: 29783
doi: 10.1093/nar/29.1.308
Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46(D1):D1062-7.
pubmed: 29165669
doi: 10.1093/nar/gkx1153
Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, et al. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136(6):665–77.
pubmed: 28349240
pmcid: 5429360
doi: 10.1007/s00439-017-1779-6
Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43.
pubmed: 32461654
pmcid: 7334197
doi: 10.1038/s41586-020-2308-7
Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, et al. A global reference for human genetic variation. Nature. 2015;526(7571):68–74.
doi: 10.1038/nature15393
GenomeAsia KC. The GenomeAsia 100K Project enables genetic discoveries across Asia. Nature. 2019;576(7785):106–11.
doi: 10.1038/s41586-019-1793-z
Thareja G, Al-Sarraj Y, Belkadi A, Almotawa M, Qatar Genome Program Research C, Suhre K, et al. Whole genome sequencing in the Middle Eastern Qatari population identifies genetic associations with 45 clinically relevant traits. Nat Commun. 2021;12(1):1250.
Martin AR, Williams E, Foulger RE, Leigh S, Daugherty LC, Niblock O, et al. PanelApp crowdsources expert knowledge to establish consensus diagnostic gene panels. Nat Genet. 2019;51(11):1560–5.
pubmed: 31676867
doi: 10.1038/s41588-019-0528-2
Bell CJ, Dinwiddie DL, Miller NA, Hateley SL, Ganusova EE, Mudge J, et al. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci Transl Med. 2011;3(65):65ra4.
pubmed: 21228398
pmcid: 3740116
doi: 10.1126/scitranslmed.3001756
Amorim CEG, Gao Z, Baker Z, Diesel JF, Simons YB, Haque IS, et al. The population genetics of human disease: the case of recessive, lethal mutations. PLoS Genet. 2017;13(9):e1006915.
pubmed: 28957316
pmcid: 5619689
doi: 10.1371/journal.pgen.1006915
Miller DT, Lee K, Abul-Husn NS, Amendola LM, Brothers K, Chung WK, et al. ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2022;24(7):1407–14.
pubmed: 35802134
doi: 10.1016/j.gim.2022.04.006
Schmitz MJ, Aarabi M, Bashar A, Rajkovic A, Gregg AR, Yatsenko SA. Carrier frequency of autosomal recessive genetic conditions in diverse populations: lessons learned from the genome aggregation database. Clin Genet. 2022;102(2):87–97.
pubmed: 35532184
doi: 10.1111/cge.14148
Gregg AR, Aarabi M, Klugman S, Leach NT, Bashford MT, Goldwaser T, et al. Screening for autosomal recessive and X-linked conditions during pregnancy and preconception: a practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021;23(10):1793–806.
pubmed: 34285390
pmcid: 8488021
doi: 10.1038/s41436-021-01203-z
Saleheen D, Natarajan P, Armean IM, Zhao W, Rasheed A, Khetarpal SA, et al. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature. 2017;544(7649):235–9.
pubmed: 28406212
pmcid: 5600291
doi: 10.1038/nature22034
Coucke PJ, Willaert A, Wessels MW, Callewaert B, Zoppi N, De Backer J, et al. Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome. Nat Genet. 2006;38(4):452–7.
pubmed: 16550171
doi: 10.1038/ng1764
Alazami AM, Al-Saif A, Al-Semari A, Bohlega S, Zlitni S, Alzahrani F, et al. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet. 2008;83(6):684–91.
pubmed: 19026396
pmcid: 2668059
doi: 10.1016/j.ajhg.2008.10.018
Abdul Wahab A, Al Thani G, Dawod ST, Kambouris M, Al Hamed M. Heterogeneity of the cystic fibrosis phenotype in a large kindred family in Qatar with cystic fibrosis mutation (I1234V). J Trop Pediatr. 2001;47(2):110–2.
pubmed: 11336127
doi: 10.1093/tropej/47.2.110a
Tadmouri GO, Ali MTA, Ali SAH, Khaja NA. CTGA: the database for genetic disorders in Arab populations. Nucleic Acids Res. 2006;34(Database issue):D602-6.
pubmed: 16381941
doi: 10.1093/nar/gkj015
King S, Germeshausen M, Strauss G, Welte K, Ballmaier M. Congenital amegakaryocytic thrombocytopenia: a retrospective clinical analysis of 20 patients. Br J Haematol. 2005;131(5):636–44.
pubmed: 16351641
doi: 10.1111/j.1365-2141.2005.05819.x
Bejjani BA, Stockton DW, Lewis RA, Tomey KF, Dueker DK, Jabak M, et al. Multiple CYP1B1 mutations and incomplete penetrance in an inbred population segregating primary congenital glaucoma suggest frequent de novo events and a dominant modifier locus. Hum Mol Genet. 2000;9(3):367–74.
pubmed: 10655546
doi: 10.1093/hmg/9.3.367
Wolfe LA, Finegold DN, Vockley J, Walters N, Chambaz C, Suormala T, et al. Potential misdiagnosis of 3-methylcrotonyl-coenzyme A carboxylase deficiency associated with absent or trace urinary 3-methylcrotonylglycine. Pediatrics. 2007;120(5):e1335-40.
pubmed: 17908719
doi: 10.1542/peds.2007-0674
Lee SJ, Lee DH, Yoo HW, Koo SK, Park ES, Park JW, et al. Identification and functional analysis of cystathionine beta-synthase gene mutations in patients with homocystinuria. J Hum Genet. 2005;50(12):648–54.
pubmed: 16205833
doi: 10.1007/s10038-005-0312-2
U. Basmanav FB, Cau L, Tafazzoli A, Mechin MC, Wolf S, Romano MT, et al. Mutations in three genes encoding proteins involved in hair shaft formation cause uncombable hair syndrome. Am J Hum Genet. 2016;99(6):1292–304.
pubmed: 27866708
pmcid: 5142115
doi: 10.1016/j.ajhg.2016.10.004
Huff MW, Hegele RA. Apolipoprotein C-III: going back to the future for a lipid drug target. Circ Res. 2013;112(11):1405–8.
pubmed: 23704213
doi: 10.1161/CIRCRESAHA.113.301464
Kelsell DP, Dunlop J, Stevens HP, Lench NJ, Liang JN, Parry G, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness. Nature. 1997;387(6628):80–3.
pubmed: 9139825
doi: 10.1038/387080a0
Cheng JB, Levine MA, Bell NH, Mangelsdorf DJ, Russell DW. Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase. Proc Natl Acad Sci U A. 2004;101(20):7711–5.
doi: 10.1073/pnas.0402490101
Kraus JP. Komrower Lecture. Molecular basis of phenotype expression in homocystinuria. J Inherit Metab Dis. 1994;17(4):383–90.
pubmed: 7967489
doi: 10.1007/BF00711354
Zeitz C, Kloeckener-Gruissem B, Forster U, Kohl S, Magyar I, Wissinger B, et al. Mutations in CABP4, the gene encoding the Ca2+-binding protein 4, cause autosomal recessive night blindness. Am J Hum Genet. 2006;79(4):657–67.
pubmed: 16960802
pmcid: 1592568
doi: 10.1086/508067
Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet. 1997;6(4):641–7.
pubmed: 9097971
doi: 10.1093/hmg/6.4.641
Davis CG, Lehrman MA, Russell DW, Anderson RG, Brown MS, Goldstein JL. The J.D. mutation in familial hypercholesterolemia: amino acid substitution in cytoplasmic domain impedes internalization of LDL receptors. Cell. 1986;45(1):15–24.
pubmed: 3955657
doi: 10.1016/0092-8674(86)90533-7
Wang L, Fan C, Topol SE, Topol EJ, Wang Q. Mutation of MEF2A in an inherited disorder with features of coronary artery disease. Science. 2003;302(5650):1578–81.
pubmed: 14645853
pmcid: 1618876
doi: 10.1126/science.1088477
Pollak MR, Brown EM, Chou YH, Hebert SC, Marx SJ, Steinmann B, et al. Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Cell. 1993;75(7):1297–303.
pubmed: 7916660
doi: 10.1016/0092-8674(93)90617-Y
Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, et al. Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family. Nat Genet. 1997;15(1):21–9.
pubmed: 8988164
doi: 10.1038/ng0197-21
Bolduc V, Marlow G, Boycott KM, Saleki K, Inoue H, Kroon J, et al. Recessive mutations in the putative calcium-activated chloride channel Anoctamin 5 cause proximal LGMD2L and distal MMD3 muscular dystrophies. Am J Hum Genet. 2010;86(2):213–21.
pubmed: 20096397
pmcid: 2820170
doi: 10.1016/j.ajhg.2009.12.013
Schessl J, Kress W, Schoser B. Novel ANO5 mutations causing hyper-CK-emia, limb girdle muscular weakness and Miyoshi type of muscular dystrophy. Muscle Nerve. 2012;45(5):740–2.
pubmed: 22499103
doi: 10.1002/mus.23281
Vorobelova L, Dankova Z, Candrakova-Cernanova V, Falbova D, Cvicelova M, Benus R, et al. Association of the ESR1 polymorphism with menopause and MLXIPL genetic variant influence serum uric acid levels in Slovak midlife women. Menopause. 2019;26(10):1185–92.
pubmed: 31268920
doi: 10.1097/GME.0000000000001371
Kim HA, Park WJ, Jeong HS, Lee HE, Lee SH, Kwon NS, et al. Leucine-rich glioma inactivated 3 regulates adipogenesis through ADAM23. Biochim Biophys Acta. 2012;1821(6):914–22.
pubmed: 22405860
doi: 10.1016/j.bbalip.2012.02.010
Fernandez-Real JM, McClain D, Manco M. Mechanisms linking glucose homeostasis and iron metabolism toward the onset and progression of type 2 diabetes. Diabetes Care. 2015;38(11):2169–76.
pubmed: 26494808
doi: 10.2337/dc14-3082
Barbier-Torres L, Fortner KA, Iruzubieta P, Delgado TC, Giddings E, Chen Y, et al. Silencing hepatic MCJ attenuates non-alcoholic fatty liver disease (NAFLD) by increasing mitochondrial fatty acid oxidation. Nat Commun. 2020;11(1):3360.
pubmed: 32620763
pmcid: 7334216
doi: 10.1038/s41467-020-16991-2
Ruth KS, Day FR, Tyrrell J, Thompson DJ, Wood AR, Mahajan A, et al. Using human genetics to understand the disease impacts of testosterone in men and women. Nat Med. 2020;26(2):252–8.
pubmed: 32042192
pmcid: 7025895
doi: 10.1038/s41591-020-0751-5
Kato N, Tamada T, Nabika T, Ueno K, Gotoda T, Matsumoto C, et al. Identification of quantitative trait loci for serum cholesterol levels in stroke-prone spontaneously hypertensive rats. Arter Thromb Vasc Biol. 2000;20(1):223–9.
doi: 10.1161/01.ATV.20.1.223
Kwiatkowski DP. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet. 2005;77(2):171–92.
pubmed: 16001361
pmcid: 1224522
doi: 10.1086/432519
Gabriel SE, Brigman KN, Koller BH, Boucher RC, Stutts MJ. Cystic fibrosis heterozygote resistance to cholera toxin in the cystic fibrosis mouse model. Science. 1994;266(5182):107–9.
pubmed: 7524148
doi: 10.1126/science.7524148
Rausell A, Luo Y, Lopez M, Seeleuthner Y, Rapaport F, Favier A, et al. Common homozygosity for predicted loss-of-function variants reveals both redundant and advantageous effects of dispensable human genes. Proc Natl Acad Sci U A. 2020;117(24):13626–36.
doi: 10.1073/pnas.1917993117
Narasimhan VM, Hunt KA, Mason D, Baker CL, Karczewski KJ, Barnes MR, et al. Health and population effects of rare gene knockouts in adult humans with related parents. Science. 2016;352(6284):474–7.
pubmed: 26940866
pmcid: 4985238
doi: 10.1126/science.aac8624
Fatumo S, Chikowore T, Choudhury A, Ayub M, Martin AR, Kuchenbaecker K. A roadmap to increase diversity in genomic studies. Nat Med. 2022;28(2):243–50.
pubmed: 35145307
pmcid: 7614889
doi: 10.1038/s41591-021-01672-4
Mohammad T, Xue Y, Evison M, Tyler-Smith C. Genetic structure of nomadic Bedouin from Kuwait. Hered Edinb. 2009;103(5):425–33.
doi: 10.1038/hdy.2009.72