Centre for Eye Research Australia (CERA) - Research Publications

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    Seeing the impact of the Glaucoma Inheritance Study in Tasmania after 25 years
    Mackey, DA ; Craig, JE ; Hewitt, AW (WILEY, 2019-07-01)
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    The genetic and clinical landscape of nanophthalmos and posterior microphthalmos in an Australian cohort
    Siggs, OM ; Awadalla, MS ; Souzeau, E ; Staffieri, SE ; Kearns, LS ; Laurie, K ; Kuot, A ; Qassim, A ; Edwards, TL ; Coote, MA ; Mancel, E ; Walland, MJ ; Dondey, J ; Galanopoulous, A ; Casson, RJ ; Mills, RA ; MacArthur, DG ; Ruddle, JB ; Burdon, KP ; Craig, JE (WILEY, 2020-05-01)
    Nanophthalmos and posterior microphthalmos are ocular abnormalities in which both eyes are abnormally small, and typically associated with extreme hyperopia. We recruited 40 individuals from 13 kindreds with nanophthalmos or posterior microphthalmos, with 12 probands subjected to exome sequencing. Nine probands (69.2%) were assigned a genetic diagnosis, with variants in MYRF, TMEM98, MFRP, and PRSS56. Two of four PRSS56 families harbored the previously described c.1066dupC variant implicated in over half of all reported PRSS56 kindreds, with different surrounding haplotypes in each family suggesting a mutational hotspot. Individuals with a genetic diagnosis had shorter mean axial lengths and higher hyperopia than those without, with recessive forms associated with the most extreme phenotypes. These findings detail the genetic architecture of nanophthalmos and posterior microphthalmos in a cohort of predominantly European ancestry, their relative clinical phenotypes, and highlight the shared genetic architecture of rare and common disorders of refractive error.
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    Family-Based Genome-Wide Association Study of South Indian Pedigrees Supports WNT7B as a Central Corneal Thickness Locus
    Fan, BJ ; Chen, X ; Sondhi, N ; Sharmila, PF ; Soumittra, N ; Sripriya, S ; Sacikala, S ; Asokan, R ; Friedman, DS ; Pasquale, LR ; Gao, XR ; Vijaya, L ; Bailey, JC ; Vitart, V ; MacGregor, S ; Hammond, CJ ; Khor, CC ; Haines, JL ; George, R ; Wiggs, JL (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2018-05-01)
    Purpose: To identify genetic risk factors contributing to central corneal thickness (CCT) in individuals from South India, a population with a high prevalence of ocular disorders. Methods: One hundred ninety-five individuals from 15 large South Indian pedigrees were genotyped using the Omni2.5 bead array. Family-based association for CCT was conducted using the score test in MERLIN. Results: Genome-wide association study (GWAS) identified strongest association for single nucleotide polymorphisms (SNPs) in the first intron of WNT7B and CCT (top SNP rs9330813; β = -0.57, 95% confidence interval [CI]: -0.78 to -0.36; P = 1.7 × 10-7). We further investigated rs9330813 in a Latino cohort and four independent European cohorts. A meta-analysis of these data sets demonstrated statistically significant association between rs9330813 and CCT (β = -3.94, 95% CI: -5.23 to -2.66; P = 1.7 × 10-9). WNT7B SNPs located in the same genomic region that includes rs9330813 have previously been associated with CCT in Latinos but with other ocular quantitative traits related to myopia (corneal curvature and axial length) in a Japanese population (rs10453441 and rs200329677). To evaluate the specificity of the observed WNT7B association with CCT in the South Indian families, we completed an ocular phenome-wide association study (PheWAS) for the top WNT7B SNPs using 45 ocular traits measured in these same families including corneal curvature and axial length. The ocular PheWAS results indicate that in the South Indian families WNT7B SNPs are primarily associated with CCT. Conclusions: The results indicate robust evidence for association between WNT7B SNPs and CCT in South Indian pedigrees, and suggest that WNT7B SNPs can have population-specific effects on ocular quantitative traits.
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    Genome-wide association analysis identifies TXNRD2, ATXN2 and FOXC1 as susceptibility loci for primary open-angle glaucoma
    Bailey, JNC ; Loomis, SJ ; Kang, JH ; Allingham, RR ; Gharahkhani, P ; Khor, CC ; Burdon, KP ; Aschard, H ; Chasman, DI ; Igo, RP ; Hysi, PG ; Glastonbury, CA ; Ashley-Koch, A ; Brilliant, M ; Brown, AA ; Budenz, DL ; Buil, A ; Cheng, C-Y ; Choi, H ; Christen, WG ; Curhan, G ; De Vivo, I ; Fingert, JH ; Foster, PJ ; Fuchs, C ; Gaasterland, D ; Gaasterland, T ; Hewitt, AW ; Hu, F ; Hunter, DJ ; Khawaja, AP ; Lee, RK ; Li, Z ; Lichter, PR ; Mackey, DA ; McGuffin, P ; Mitchell, P ; Moroi, SE ; Perera, SA ; Pepper, KW ; Qi, Q ; Realini, T ; Richards, JE ; Ridker, PM ; Rimm, E ; Ritch, R ; Ritchie, M ; Schuman, JS ; Scott, WK ; Singh, K ; Sit, AJ ; Song, YE ; Tamimi, RM ; Topouzis, F ; Viswanathan, AC ; Verma, SS ; Vollrath, D ; Wang, JJ ; Weisschuh, N ; Wissinger, B ; Wollstein, G ; Wong, TY ; Yaspan, BL ; Zack, DJ ; Zhang, K ; Weinreb, RN ; Pericak-Vance, MA ; Small, K ; Hammond, CJ ; Aung, T ; Liu, Y ; Vithana, EN ; MacGregor, S ; Craig, JE ; Kraftl, P ; Howell, G ; Hauser, MA ; Pasguale, LR ; Haines, JL ; Wiggs, JL (NATURE PUBLISHING GROUP, 2016-02-01)
    Primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide. To identify new susceptibility loci, we performed meta-analysis on genome-wide association study (GWAS) results from eight independent studies from the United States (3,853 cases and 33,480 controls) and investigated the most significantly associated SNPs in two Australian studies (1,252 cases and 2,592 controls), three European studies (875 cases and 4,107 controls) and a Singaporean Chinese study (1,037 cases and 2,543 controls). A meta-analysis of the top SNPs identified three new associated loci: rs35934224[T] in TXNRD2 (odds ratio (OR) = 0.78, P = 4.05 × 10(-11)) encoding a mitochondrial protein required for redox homeostasis; rs7137828[T] in ATXN2 (OR = 1.17, P = 8.73 × 10(-10)); and rs2745572[A] upstream of FOXC1 (OR = 1.17, P = 1.76 × 10(-10)). Using RT-PCR and immunohistochemistry, we show TXNRD2 and ATXN2 expression in retinal ganglion cells and the optic nerve head. These results identify new pathways underlying POAG susceptibility and suggest new targets for preventative therapies.
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    A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants
    Fritsche, LG ; Igl, W ; Bailey, JNC ; Grassmann, F ; Sengupta, S ; Bragg-Gresham, JL ; Burdon, KP ; Hebbring, SJ ; Wen, C ; Gorski, M ; Kim, IK ; Cho, D ; Zack, D ; Souied, E ; Scholl, HPN ; Bala, E ; Lee, KE ; Hunter, DJ ; Sardell, RJ ; Mitchell, P ; Merriam, JE ; Cipriani, V ; Hoffman, JD ; Schick, T ; Lechanteur, YTE ; Guymer, RH ; Johnson, MP ; Jiang, Y ; Stanton, CM ; Buitendijk, GHS ; Zhan, X ; Kwong, AM ; Boleda, A ; Brooks, M ; Gieser, L ; Ratnapriya, R ; Branham, KE ; Foerster, JR ; Heckenlively, JR ; Othman, MI ; Vote, BJ ; Liang, HH ; Souzeau, E ; McAllister, IL ; Isaacs, T ; Hall, J ; Lake, S ; Mackey, DA ; Constable, IJ ; Craig, JE ; Kitchner, TE ; Yang, Z ; Su, Z ; Luo, H ; Chen, D ; Hong, O ; Flagg, K ; Lin, D ; Mao, G ; Ferreyra, H ; Starke, K ; von Strachwitz, CN ; Wolf, A ; Brandl, C ; Rudolph, G ; Olden, M ; Morrison, MA ; Morgan, DJ ; Schu, M ; Ahn, J ; Silvestri, G ; Tsironi, EE ; Park, KH ; Farrer, LA ; Orlin, A ; Brucker, A ; Li, M ; Curcio, CA ; Mohand-Said, S ; Sahel, J-M ; Audo, I ; Benchaboune, M ; Cree, AJ ; Rennie, CA ; Goverdhan, SV ; Grunin, M ; Hagbi-Levi, S ; Campochiaro, P ; Katsanis, N ; Holz, FG ; Blond, F ; Blanche, H ; Deleuze, J-F ; Igo, RP ; Truitt, B ; Peachey, NS ; Meuer, SM ; Myers, CE ; Moore, EL ; Klein, R ; Hauser, MA ; Postel, EA ; Courtenay, MD ; Schwartz, SG ; Kovach, JL ; Scott, WK ; Liew, G ; Tan, AG ; Gopinath, B ; Merriam, JC ; Smith, RT ; Khan, JC ; Shahid, H ; Moore, AT ; McGrath, JA ; Laux, R ; Brantley, MA ; Agarwal, A ; Ersoy, L ; Caramoy, A ; Langmann, T ; Saksens, NTM ; de Jong, EK ; Hoyng, CB ; Cain, MS ; Richardson, AJ ; Martin, TM ; Blangero, J ; Weeks, DE ; Dhillon, B ; van Duijn, CM ; Doheny, KF ; Romm, J ; Klaver, CCW ; Hayward, C ; Gorin, MB ; Klein, ML ; Baird, PN ; den Hollander, AI ; Fauser, S ; Yates, JRW ; Allikmets, R ; Wang, JJ ; Schaumberg, DA ; Klein, BEK ; Hagstrom, SA ; Chowers, I ; Lotery, AJ ; Leveillard, T ; Zhang, K ; Brilliant, MH ; Hewitt, AW ; Swaroop, A ; Chew, EY ; Pericak-Vance, MA ; DeAngelis, M ; Stambolian, D ; Haines, JL ; Iyengar, SK ; Weber, BHF ; Abecasis, GR ; Heid, IM (NATURE PUBLISHING GROUP, 2016-02-01)
    Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly, with limited therapeutic options. Here we report on a study of >12 million variants, including 163,714 directly genotyped, mostly rare, protein-altering variants. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P < 5 × 10(-8)) distributed across 34 loci. Although wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first genetic association signal specific to wet AMD, near MMP9 (difference P value = 4.1 × 10(-10)). Very rare coding variants (frequency <0.1%) in CFH, CFI and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes.
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    Genome-wide association study for refractive astigmatism reveals genetic co-determination with spherical equivalent refractive error: the CREAM consortium
    Li, Q ; Wojciechowski, R ; Simpson, CL ; Hysi, PG ; Verhoeven, VJM ; Ikram, MK ; Hoehn, R ; Vitart, V ; Hewitt, AW ; Oexle, K ; Makela, K-M ; MacGregor, S ; Pirastu, M ; Fan, Q ; Cheng, C-Y ; St Pourcain, B ; McMahon, G ; Kemp, JP ; Northstone, K ; Rahi, JS ; Cumberland, PM ; Martin, NG ; Sanfilippo, PG ; Lu, Y ; Wang, YX ; Hayward, C ; Polasek, O ; Campbell, H ; Bencic, G ; Wright, AF ; Wedenoja, J ; Zeller, T ; Schillert, A ; Mirshahi, A ; Lackner, K ; Yip, SP ; Yap, MKH ; Ried, JS ; Gieger, C ; Murgia, F ; Wilson, JF ; Fleck, B ; Yazar, S ; Vingerling, JR ; Hofman, A ; Uitterlinden, A ; Rivadeneira, F ; Amin, N ; Karssen, L ; Oostra, BA ; Zhou, X ; Teo, Y-Y ; Tai, ES ; Vithana, E ; Barathi, V ; Zheng, Y ; Siantar, RG ; Neelam, K ; Shin, Y ; Lam, J ; Yonova-Doing, E ; Venturini, C ; Hosseini, SM ; Wong, H-S ; Lehtimaki, T ; Kahonen, M ; Raitakari, O ; Timpson, NJ ; Evans, DM ; Khor, C-C ; Aung, T ; Young, TL ; Mitchell, P ; Klein, B ; van Duijn, CM ; Meitinger, T ; Jonas, JB ; Baird, PN ; Mackey, DA ; Wong, TY ; Saw, S-M ; Parssinen, O ; Stambolian, D ; Hammond, CJ ; Klaver, CCW ; Williams, C ; Paterson, AD ; Bailey-Wilson, JE ; Guggenheim, JA (SPRINGER, 2015-02-01)
    To identify genetic variants associated with refractive astigmatism in the general population, meta-analyses of genome-wide association studies were performed for: White Europeans aged at least 25 years (20 cohorts, N = 31,968); Asian subjects aged at least 25 years (7 cohorts, N = 9,295); White Europeans aged <25 years (4 cohorts, N = 5,640); and all independent individuals from the above three samples combined with a sample of Chinese subjects aged <25 years (N = 45,931). Participants were classified as cases with refractive astigmatism if the average cylinder power in their two eyes was at least 1.00 diopter and as controls otherwise. Genome-wide association analysis was carried out for each cohort separately using logistic regression. Meta-analysis was conducted using a fixed effects model. In the older European group the most strongly associated marker was downstream of the neurexin-1 (NRXN1) gene (rs1401327, P = 3.92E-8). No other region reached genome-wide significance, and association signals were lower for the younger European group and Asian group. In the meta-analysis of all cohorts, no marker reached genome-wide significance: The most strongly associated regions were, NRXN1 (rs1401327, P = 2.93E-07), TOX (rs7823467, P = 3.47E-07) and LINC00340 (rs12212674, P = 1.49E-06). For 34 markers identified in prior GWAS for spherical equivalent refractive error, the beta coefficients for genotype versus spherical equivalent, and genotype versus refractive astigmatism, were highly correlated (r = -0.59, P = 2.10E-04). This work revealed no consistent or strong genetic signals for refractive astigmatism; however, the TOX gene region previously identified in GWAS for spherical equivalent refractive error was the second most strongly associated region. Analysis of additional markers provided evidence supporting widespread genetic co-susceptibility for spherical and astigmatic refractive errors.
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    Assessment of polygenic effects links primary open-angle glaucoma and age-related macular degeneration
    Cuellar-Partida, G ; Craig, JE ; Burdon, KP ; Wang, JJ ; Vote, BJ ; Souzeau, E ; McAllister, IL ; Isaacs, T ; Lake, S ; Mackey, DA ; Constable, IJ ; Mitchell, P ; Hewitt, AW ; MacGregor, S (NATURE PUBLISHING GROUP, 2016-05-31)
    Primary open-angle glaucoma (POAG) and age-related macular degeneration (AMD) are leading causes of irreversible blindness. Several loci have been mapped using genome-wide association studies. Until very recently, there was no recognized overlap in the genetic contribution to AMD and POAG. At genome-wide significance level, only ABCA1 harbors associations to both diseases. Here, we investigated the genetic architecture of POAG and AMD using genome-wide array data. We estimated the heritability for POAG (h(2)g = 0.42 ± 0.09) and AMD (h(2)g = 0.71 ± 0.08). Removing known loci for POAG and AMD decreased the h(2)g estimates to 0.36 and 0.24, respectively. There was evidence for a positive genetic correlation between POAG and AMD (rg = 0.47 ± 0.25) which remained after removing known loci (rg = 0.64 ± 0.31). We also found that the genetic correlation between sexes for POAG was likely to be less than 1 (rg = 0.33 ± 0.24), suggesting that differences of prevalence among genders may be partly due to heritable factors.
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    Meta-analysis of gene-environment-wide association scans accounting for education level identifies additional loci for refractive error
    Fan, Q ; Verhoeven, VJM ; Wojciechowski, R ; Barathi, VA ; Hysi, PG ; Guggenheim, JA ; Hoehn, R ; Vitart, V ; Khawaja, AP ; Yamashiro, K ; Hosseini, SM ; Lehtimaki, T ; Lu, Y ; Haller, T ; Xie, J ; Delcourt, C ; Pirastu, M ; Wedenoja, J ; Gharahkhani, P ; Venturini, C ; Miyake, M ; Hewitt, AW ; Guo, X ; Mazur, J ; Huffman, JE ; Williams, KM ; Polasek, O ; Campbell, H ; Rudan, I ; Vatavuk, Z ; Wilson, JF ; Joshi, PK ; McMahon, G ; St Pourcain, B ; Evans, DM ; Simpson, CL ; Schwantes-An, T-H ; Igo, RP ; Mirshahi, A ; Cougnard-Gregoire, A ; Bellenguez, C ; Blettner, M ; Raitakari, O ; Kaehoenen, M ; Seppala, I ; Zeller, T ; Meitinger, T ; Ried, JS ; Gieger, C ; Portas, L ; van Leeuwen, EM ; Amin, N ; Uitterlinden, AG ; Rivadeneira, F ; Hofman, A ; Vingerling, JR ; Wang, YX ; Wang, X ; Boh, ET-H ; Ikram, MK ; Sabanayagam, C ; Gupta, P ; Tan, V ; Zhou, L ; Ho, CEH ; Lim, W ; Beuerman, RW ; Siantar, R ; Tai, E-S ; Vithana, E ; Mihailov, E ; Khor, C-C ; Hayward, C ; Luben, RN ; Foster, PJ ; Klein, BEK ; Klein, R ; Wong, H-S ; Mitchell, P ; Metspalu, A ; Aung, T ; Young, TL ; He, M ; Paerssinen, O ; van Duijn, CM ; Wang, JJ ; Williams, C ; Jonas, JB ; Teo, Y-Y ; David, AMM ; Oexle, K ; Yoshimura, N ; Paterson, AD ; Pfeiffer, N ; Wong, T-Y ; Baird, PN ; Stambolian, D ; Bailey-Wilson, JE ; Cheng, C-Y ; Hammond, CJ ; Klaver, CCW ; Saw, S-M ; Rahi, JS ; Korobelnik, J-F ; Kemp, JP ; Timpson, NJ ; Smith, GD ; Craig, JE ; Burdon, KP ; Fogarty, RD ; Iyengar, SK ; Chew, E ; Janmahasatian, S ; Martin, NG ; MacGregor, S ; Xu, L ; Schache, M ; Nangia, V ; Panda-Jonas, S ; Wright, AF ; Fondran, JR ; Lass, JH ; Feng, S ; Zhao, JH ; Khaw, K-T ; Wareham, NJ ; Rantanen, T ; Kaprio, J ; Pang, CP ; Chen, LJ ; Tam, PO ; Jhanji, V ; Young, AL ; Doering, A ; Raffel, LJ ; Cotch, M-F ; Li, X ; Yip, SP ; Yap, MKH ; Biino, G ; Vaccargiu, S ; Fossarello, M ; Fleck, B ; Yazar, S ; Tideman, JWL ; Tedja, M ; Deangelis, MM ; Morrison, M ; Farrer, L ; Zhou, X ; Chen, W ; Mizuki, N ; Meguro, A ; Makela, KM (NATURE PUBLISHING GROUP, 2016-04-01)
    Myopia is the most common human eye disorder and it results from complex genetic and environmental causes. The rapidly increasing prevalence of myopia poses a major public health challenge. Here, the CREAM consortium performs a joint meta-analysis to test single-nucleotide polymorphism (SNP) main effects and SNP × education interaction effects on refractive error in 40,036 adults from 25 studies of European ancestry and 10,315 adults from 9 studies of Asian ancestry. In European ancestry individuals, we identify six novel loci (FAM150B-ACP1, LINC00340, FBN1, DIS3L-MAP2K1, ARID2-SNAT1 and SLC14A2) associated with refractive error. In Asian populations, three genome-wide significant loci AREG, GABRR1 and PDE10A also exhibit strong interactions with education (P<8.5 × 10(-5)), whereas the interactions are less evident in Europeans. The discovery of these loci represents an important advance in understanding how gene and environment interactions contribute to the heterogeneity of myopia.
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    Glaucoma spectrum and age-related prevalence of individuals with FOXC1 and PITX2 variants
    Souzeau, E ; Siggs, OM ; Zhou, T ; Galanopoulos, A ; Hodson, T ; Taranath, D ; Mills, RA ; Landers, J ; Pater, J ; Smith, JE ; Elder, JE ; Rait, JL ; Giles, P ; Phakey, V ; Staffieri, SE ; Kearns, LS ; Dubowsky, A ; Mackey, DA ; Hewitt, AW ; Ruddle, JB ; Burdon, KP ; Craig, JE (SPRINGERNATURE, 2017-06-01)
    Variation in FOXC1 and PITX2 is associated with Axenfeld-Rieger syndrome, characterised by structural defects of the anterior chamber of the eye and a range of systemic features. Approximately half of all affected individuals will develop glaucoma, but the age at diagnosis and the phenotypic spectrum have not been well defined. As phenotypic heterogeneity is common, we aimed to delineate the age-related penetrance and the full phenotypic spectrum of glaucoma in FOXC1 or PITX2 carriers recruited through a national disease registry. All coding exons of FOXC1 and PITX2 were directly sequenced and multiplex ligation-dependent probe amplification was performed to detect copy number variation. The cohort included 53 individuals from 24 families with disease-associated FOXC1 or PITX2 variants, including one individual diagnosed with primary congenital glaucoma and five with primary open-angle glaucoma. The overall prevalence of glaucoma was 58.5% and was similar for both genes (53.3% for FOXC1 vs 60.9% for PITX2, P=0.59), however, the median age at glaucoma diagnosis was significantly lower in FOXC1 (6.0±13.0 years) compared with PITX2 carriers (18.0±10.6 years, P=0.04). The penetrance at 10 years old was significantly lower in PITX2 than FOXC1 carriers (13.0% vs 42.9%, P=0.03) but became comparable at 25 years old (71.4% vs 57.7%, P=0.38). These findings have important implications for the genetic counselling of families affected by Axenfeld-Rieger syndrome, and also suggest that FOXC1 and PITX2 contribute to the genetic architecture of primary glaucoma subtypes.
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    Ethical Considerations for the Return of Incidental Findings in Ophthalmic Genomic Research
    Souzeau, E ; Burdon, KP ; Mackey, DA ; Hewitt, AW ; Savarirayan, R ; Otlowski, M ; Craig, JE (ASSOC RESEARCH VISION OPHTHALMOLOGY INC, 2016-01-01)
    Whole genome and whole exome sequencing technologies are being increasingly used in research. However, they have the potential to identify incidental findings (IF), findings not related to the indication of the test, raising questions regarding researchers' responsibilities toward the return of this information to participants. In this study we discuss the ethical considerations related to the return of IF to research participants, emphasizing that the type of the study matters and describing the current practice standards. There are currently no legal obligations for researchers to return IF to participants, but some viewpoints consider that researchers might have an ethical one to return IF of clinical validity and clinical utility and that are actionable. The reality is that most IF are complex to interpret, especially since they were not the indication of the test. The clinical utility often depends on the participants' preferences, which can be challenging to conciliate and relies on participants' understanding. In summary, in the context of a lack of clear guidance, researchers need to have a clear plan for the disclosure or nondisclosure of IF from genomic research, balancing their research goals and resources with the participants' rights and their duty not to harm.