{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T09:38:46Z","timestamp":1778233126813,"version":"3.51.4"},"update-to":[{"DOI":"10.12688\/f1000research.109488.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000}}],"reference-count":62,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T00:00:00Z","timestamp":1709510400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["f1000research.com"],"crossmark-restriction":false},"short-container-title":["F1000Res"],"abstract":"<ns3:p>\n                    Background Bovine congestive heart failure (BCHF) has become increasingly prevalent among feedlot cattle in the Western Great Plains of North America with up to 7% mortality in affected herds. BCHF is an untreatable complex condition involving pulmonary hypertension that culminates in right ventricular failure and death. Genes associated with BCHF in feedlot cattle have not been previously identified. Our aim was to search for genomic regions associated with this disease. Methods A retrospective, matched case-control design with 102 clinical BCHF cases and their unaffected pen mates was used in a genome-wide association study. Paired nominal data from approximately 560,000 filtered single nucleotide polymorphisms (SNPs) were analyzed with McNemar\u2019s test. Results Two independent genomic regions were identified as having the most significant association with BCHF: the arrestin domain-containing protein 3 gene (\n                    <ns3:italic>ARRDC3<\/ns3:italic>\n                    ), and the nuclear factor IA gene (\n                    <ns3:italic>NFIA<\/ns3:italic>\n                    , mid-\n                    <ns3:italic>p<\/ns3:italic>\n                    -values, 1x10\u22128 and 2x10 \u22127, respectively). Animals with two copies of risk alleles at either gene were approximately eight-fold more likely to have BCHF than their matched pen mates with either one or zero risk alleles at both genes (CI 95 = 3-17). Further, animals with two copies of risk alleles at both genes were 28-fold more likely to have BCHF than all others (\n                    <ns3:italic>p<\/ns3:italic>\n                    -value = 1\u00d710\u22127, CI95 = 4-206). A missense variant in\n                    <ns3:italic>ARRDC3<\/ns3:italic>\n                    (C182Y) represents a potential functional variant since the C182 codon is conserved among all other jawed vertebrate species observed. A two-SNP test with markers in both genes showed 29% of 273 BCHF cases had homozygous risk genotypes in both genes, compared to 2.5% in 198 similar unaffected feedlot cattle. This and other DNA tests may be useful for identifying feedlot animals with the highest risk for BCHF in the environments described here. Conclusions Although pathogenic roles for variants in the\n                    <ns3:italic>ARRDC3<\/ns3:italic>\n                    and\n                    <ns3:italic>NFIA<\/ns3:italic>\n                    genes are unknown, their discovery facilitates classifying animals by genetic risk and allows cattle producers to make informed decisions for selective breeding and animal health management.\n                  <\/ns3:p>","DOI":"10.12688\/f1000research.109488.2","type":"journal-article","created":{"date-parts":[[2024,3,4]],"date-time":"2024-03-04T05:35:08Z","timestamp":1709530508000},"page":"385","update-policy":"https:\/\/doi.org\/10.12688\/f1000research.crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["Association of ARRDC3 and NFIA variants with bovine congestive heart failure in feedlot cattle"],"prefix":"10.12688","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1386-1208","authenticated-orcid":false,"given":"Michael P.","family":"Heaton","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0129-6822","authenticated-orcid":false,"given":"Gregory P.","family":"Harhay","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adam S.","family":"Bassett","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Halden J.","family":"Clark","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jaden M.","family":"Carlson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Erin E.","family":"Jobman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helen R.","family":"Sadd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Madeline C.","family":"Pelster","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aspen M.","family":"Workman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Larry A.","family":"Kuehn","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2370-8189","authenticated-orcid":false,"given":"Theodore S.","family":"Kalbfleisch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heather","family":"Piscatelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Carrie","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Greta M.","family":"Krafsur","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dale M.","family":"Grotelueschen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0732-2590","authenticated-orcid":false,"given":"Brian L.","family":"Vander Ley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"2560","published-online":{"date-parts":[[2024,3,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1186\/s12711-017-0356-8","article-title":"Genome-wide association studies and genomic prediction of breeding values for calving performance and body conformation traits in Holstein cattle.","volume":"49","author":"M Abo-Ismail","year":"2017","journal-title":"Genet. 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Investig."}],"container-title":["F1000Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/f1000research.com\/articles\/11-385\/v2\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/11-385\/v2\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/f1000research.com\/articles\/11-385\/v2\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,25]],"date-time":"2024-04-25T07:55:12Z","timestamp":1714031712000},"score":1,"resource":{"primary":{"URL":"https:\/\/f1000research.com\/articles\/11-385\/v2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,3,4]]},"references-count":62,"URL":"https:\/\/doi.org\/10.12688\/f1000research.109488.2","relation":{"has-review":[{"id-type":"doi","id":"10.5256\/f1000research.162702.r263441","asserted-by":"subject"},{"id-type":"doi","id":"10.5256\/f1000research.162702.r263441","asserted-by":"object"},{"id-type":"doi","id":"10.5256\/f1000research.162702.r252387","asserted-by":"object"}]},"ISSN":["2046-1402"],"issn-type":[{"value":"2046-1402","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,3,4]]},"assertion":[{"value":"Indexed","URL":"https:\/\/f1000research.com\/articles\/11-385\/v2#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.5256\/f1000research.120994.r129614, Alan L. Archibald, The Roslin Institute, Royal (Dick) School of Veterinary Studies (R(D)SVS), University of Edinburgh, Midlothian, 20 Apr 2022, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/11-385\/v1#referee-response-129614","order":0,"name":"referee-response-129614","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Michael Heaton<\/b>; \n<i>Posted: 13 Feb 2024<\/i>; AUTHORS' RESPONSE TO REVIEWER 1  The authors appreciate and are grateful for both reviewers\u2019 thoughtful reviews of our article.&nbsp; Below we have provided point-by-point responses to their suggestions and comments:  \n<b>Reviewer 1, point 1:<\/b> &nbsp;\u201cSequence analysis of the \n<i>ARRDC3<\/i> locus in individuals of known BCHF phenotypes might reveal candidate causal or risk variants.\u201d  \n<b>Authors response 1:<\/b> &nbsp;&nbsp;We agree. We attempted to indicate this point in the last paragraph of the discussion.&nbsp; However, to further underscore this point and make our intentions unambiguous, we have revised the first paragraph of the discussion: \u201c\n<i>It is unknown whether the associated SNPs are merely linked to variants responsible for the elevated BCHF risk, or whether they are involved directly in pathogenesis.&nbsp; Whole genomic sequence (WGS) analyses are underway for the 102 case-control pairs of animals and may unlock further insights in the future.<\/i>\u201d&nbsp; &nbsp;The last paragraph of the discussion was also revised to emphasize this point: &nbsp;\u201c\n<i>Any novel variants with increased association would potentially represent candidates for functional variants conferring BCHF risk.&nbsp; A WGS analysis may also identify any newly associated genomic regions previously missed due to ascertainment bias in the SNP selection for the BovineHD BeadChip array.&nbsp; For these reasons, we are endeavoring to produce and analyze 15-fold WGS coverage from these 204 animals.<\/i>\u201d&nbsp;  \n<b>Reviewer 1, point 2<\/b>:\n<b> <\/b>&nbsp;\u201cIn order to link the SNP information reported in the manuscript more readily to other data sources it would be useful to add rs numbers.\u201d  \n<b>Authors response 2:<\/b>&nbsp;&nbsp; We agree and have added rs numbers to Table 2 for the 12 SNPs most associated with BCHF.&nbsp; To provide additional unique molecular information defining these 12 SNP, we also added Table 5 which includes 200 bp of adjacent context nucleotide sequence from the ARS-UCD2.1 bovine reference assembly, together with flanking SNP variants greater than 0.015 frequency as identified in a 96-member beef cattle diversity panel.&nbsp; Together, these details are important for designing accurate assays to score genotypes at SNP sites associated with BCHF in feedlots of the Western Great Plains.  \n<b>Reviewer 1, points 3 and 4: <\/b>&nbsp;\u201cThe frequencies of the ARRDC3 risk alleles as summarised in Table 4 are very high in some breeds, including Angus, Red Angus, Murray Grey and i) pose a challenge to selective breeding in these breeds to reduce the risk of BCHF and ii) raises questions about why the incidence of BCHF is not higher.\u201d  \n<b>Authors response 3 and 4: <\/b>&nbsp;We agree and have added two sequential paragraphs to the Discussion section:&nbsp; \u201c\n<i>The high frequencies of ARRDC3 and NFIA risk alleles in some affected breeds (&gt; 0.65) raise the question of why the disease prevalence is relatively low even in outbreaks (&gt; 0.07)?&nbsp; This phenomenon may be due to the multifactorial nature of complex disease.&nbsp; The development of BCHF in cattle is presumed to be influenced by exposure to non-genetic factors, such as elevation (hypoxia), extreme weather conditions, feeding schedules, ionophores, feed grade antibiotics, steroid hormone implants, and beta-adrenergic agonist feed additives (Krafsur et al, 2019, Neary et al. 2018).&nbsp; These environmental and management factors may play significant but unknown roles in disease development.&nbsp; In addition, most complex diseases are considered polygenic with variation at many genes having small effects (Khera et al. 2018).&nbsp; DNA sequence variation identified here in ARRDC3 and NFIA genomic regions may predispose cattle to BCHF under certain conditions, despite the absence of any known causal pathogenic mutations.<\/i>  \n<i>The high frequencies of risk alleles observed in some breeds also poses a challenge for selective breeding.&nbsp; Although estimates for the positive predictive value of the ARRDC3 and NFIA markers were low (0.10), the negative predictive value was quite high (0.99). Consequently, identifying breeding stock lacking these risk factors could prove useful for reducing a herd's overall risk.&nbsp; The challenge is finding sires without the ARRDC3 and NFIA risk alleles in breeds with a high prevalence of high-risk alleles.&nbsp; For instance, the largest affected breed in the United States, American Angus, has more than 300,000 bulls registered annually in its association.&nbsp; However, less than 5% (15,000) are expected to possess the optimal low-risk genotypes at both the ARRDC3 and NFIA gene regions (M. Heaton, L. Kuehn, and B. Vander Ley 2022, unpublished). To identify the best bulls for decreasing BCHF risk alleles in their herds, cattle producers may need to obtain genotypes from hundreds of candidate sires. Unfortunately, this information is not widely available for most bulls at present.&nbsp; Despite these challenges, there are a number of reasonable selection strategies that could help reduce the risk of BCHF in the long term, depending on the specific goals and circumstances of the cattle producer.<\/i> \u201c","URL":"https:\/\/f1000research.com\/articles\/11-385\/v2#referee-comment-11058","order":1,"name":"referee-comment-11058","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.120994.r129617, Cord Dr\u00f6gem\u00fcller, Institute of Genetics, Vetsuisse Faculty, University of Bern, Bern, 26 Apr 2022, version 1, 1 approved, 1 approved with reservations","URL":"https:\/\/f1000research.com\/articles\/11-385\/v1#referee-response-129617","order":2,"name":"referee-response-129617","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"<b>Michael Heaton<\/b>; \n<i>Posted: 13 Feb 2024<\/i>; AUTHORS' RESPONSE TO REVIEWER 2  The authors appreciate and are grateful for both reviewers\u2019 thoughtful reviews of our article.&nbsp; Below we have provided point-by-point responses to their suggestions and comments:  \n<b>Reviewer 2, point 1:<\/b>&nbsp; \u201cThe study aims to identify a possible genetic cause for the occurrence of BCHF in North American feedlot cattle.\u201d  \n<b>Authors response 1:<\/b>&nbsp; &nbsp;Our aim has been subtly misstated above, but in an important way.&nbsp; Our stated aim in the Abstract was \u201cto search for genomic regions associated with this disease\u201d.&nbsp; Our search was designed to test the null hypothesis that no significant association exists between HD770 SNPs tagging genomic regions and BCHF.&nbsp; We have indicated throughout the article that we are reporting the association of SNP alleles and not the pathogenic roles for \n<i>ARRDC3<\/i> and \n<i>NFIA<\/i> variants associated with BCHF.&nbsp; Our focus has been on the strength and reproducibility of the detected associations, not their likelihood of being causal.&nbsp; To underscore our stated aim, we have modified the Introduction section final paragraph to include this text:&nbsp; \u201c\u2026\n<i> <\/i>\n<i>to test the null hypothesis that significant association does not exist between haplotype tagging SNPs and BCHF.&nbsp; Our results rejected the null hypothesis and identified two distinct genomic regions harboring major genetic risk factors associated with BCHF.<\/i>\u201d  \n<b>Reviewer 2, point 2: <\/b>&nbsp;\u201cTherefore, because no genome sequence data were available, it is rather to assume that in both cases the identified SNPs are only coupled markers and hardly the molecular cause. This should be clearly differentiated in the paper.\u201d  \n<b>Authors response 2:<\/b>&nbsp;&nbsp; We agree and have modified the 4\n<sup>th<\/sup> and 5\n<sup>th<\/sup> sentences of the discussion to state: \n<i>\u201cThe most significant genome-wide associations were limited to two regions containing ARRDC3 and NFIA genes, respectively.&nbsp; In each region, multiple linked SNPs were associated with BCHF in feedlot cattle.&nbsp; It is unknown whether the associated SNPs are merely linked to variants responsible for the elevated BCHF risk, or whether they are involved directly in pathogenesis.\u201c&nbsp; <\/i>As described in our response to Reviewer 1, we underscore this point and make our intentions unambiguous in the last paragraph: &nbsp;&nbsp;\u201c\n<i>Thus, WGS analysis of the 102 case-control pairs would refine the bounds of the genomic region most strongly associated with BCHF and identify the complete set of tagging SNPs appropriate for use in genotyping by sequencing.&nbsp; Any novel variants with increased association would potentially represent candidates for functional variants conferring BCHF risk.&nbsp; A WGS analysis may also identify any newly associated genomic regions previously missed due to ascertainment bias in the SNP selection for the BovineHD BeadChip array.&nbsp; For these reasons, we are endeavoring to produce and analyze 15-fold WGS coverage from these 204 animals.<\/i>\u201d&nbsp;  \n<b>Reviewer 2, point 3:<\/b>&nbsp; \u201c'Fedlot cattle' is not a clear term outside of North America, so it would be better to speak of the breed involved (Angus?).\u201d  \n<b>Authors response 3: <\/b>&nbsp;&nbsp;We recognize that the details of North American beef production may not be well known around the world.&nbsp; Moreover, it varies greatly within the US.&nbsp;&nbsp; Feedlots may receive all types of beef, dairy, and composite cattle.&nbsp; Overall, Angus-influenced black cattle represent about 70% of the fattened cattle in the study region.&nbsp; In the method section we describe a group of 204 calves as 93% solid black, 70% castrated males, and none had visible horns.&nbsp; Although the cases were defined by clinical presentation, they seemed roughly representative of the feedlots we sampled. &nbsp;We have inserted the following sentence in the third line of the Introduction section: \u201c\n<i>Feedlot cattle in this region are typically a mix of germplasm derived from popular British and Continental European breeds with more than 60% of the animals having a black hide from Angus contributions.<\/i>\u201c  \n<b>Reviewer 2, point 4:<\/b>&nbsp; &nbsp;\u201cWere there any other pathological (histological) data on the disease?\u201d  \n<b>Authors response 4: <\/b>&nbsp;&nbsp;Systematic histological data was not collected on the 102 pairs of cases and controls.&nbsp; Tissues were collected from the clinical cases at necropsy, but the tissues of healthy controls were processed into beef and unavailable.  \n<b>Reviewer 2, point 5:<\/b>&nbsp; \u201cWhat is known about the possible inheritance of BCHF? Have segregation analyses been performed? What is the heritability?\u201d  \n<b>Authors response 5:<\/b>&nbsp; To date, there have been no reports of inheritance, segregation analysis, or heritability of clinical BCHF.&nbsp; Also, no other studies have used a BCHF phenotype to directly obtain an estimate that could correspond to our study.&nbsp; We used a clinically-defined binary phenotype to represent BCHF, specifically, end-stage congestive heart failure mortality in Western Great Plains feedlot cattle.&nbsp; By comparison all matched pen mate control animals were normal and passed their antemortem inspection at beef processing facilities.&nbsp; Thus, with only two phenotypic states, the use of variance as a convenient mathematical quantity was not appropriate for estimating heritability.&nbsp; Moreover, our BCHF study used animals raised in multiple environments and populations, while heritability is a statistical measure defined in the context of a specific environment and a specific population. &nbsp;For these and other reasons, heritability has not been measured for BCHF.&nbsp; Since our publication, a report used cardiomegaly observed at slaughter as a proxy for \u201cBCHF\u201d (Buchanan, JW et al., Front. Genet. 2023; 14:1148301).&nbsp; However, healthy animals with enlarged hearts cattle that have passed antemortem inspection do not meet our criteria for BCHF and would be considered unaffected controls in our study.  \n<b>Reviewer 2, point 6:<\/b> &nbsp;\u201cIf about 5% of feedlot cattle are at risk for BCHF, why have only about 100 affected animals been identified when over 1400000 cattle have been considered? Is the disease rarer than assumed?\u201d  \n<b>Authors response 6: <\/b>&nbsp;The 5% number is the mortality in severely affected pens of cattle.&nbsp; It was not the percentage of cattle at risk.&nbsp; &nbsp;To clarify reasons for the case enrollment rate, we have added this text to the Methods section, \u201c\n<i>The case <\/i>\n<i>enrollment rate of 102 cases per 140,000 feedlot cattle monitored (0.073%) was negatively affected by:&nbsp; 1) removal of sick animals for emergency salvage slaughter, 2) removal of matched unaffected pen mates for beef processing, 3) the rapid onset of congestive heart failure and death, 4) reluctance of overburdened personnel to commit valuable time despite the $500 indemnity offer for each matched pair identified early, and 5) exclusion of necropsied animals meeting some, but not all, of the case definition criteria.<\/i>\n<i>\u201d<\/i> &nbsp;We also suspect that the disease is underreported due to worker misclassification at necropsy.  \n<b>Reviewer 2, point 7:<\/b> The nomenclature of variants, especially the representation of ARRDC3 alleles, should necessarily follow the current recommendations, see Richards et al. 20151.  \n<b>Authors response 7: <\/b>&nbsp;The Richard et al. 2015&nbsp; article (\u201cStandards and guidelines for the interpretation of sequence variants\u201d) provides detailed criteria for classifying pathogenic variants in genes known to cause human diseases.&nbsp; As noted in Authors response 1 above, our stated aim was \u201cto search for genomic regions associated with this disease\u201d.&nbsp; We are not reporting the pathogenicity of variants in this report.&nbsp; We have added the rs numbers for the variants highlighted in Table 2 and added context sequence information in a new Table 5.  \n<b>Reviewer 2 point 8:<\/b> The intronic variant in the NFIA gene remains functionally absolutely unclear, therefore talk about a linked marker rather than a possible causal variant.  \n<b>Authors response 8: <\/b>&nbsp;Although it is not clear which sentence in the manuscript that Reviewer 2 is referring, we agree.&nbsp; Other than the possibility of the \n<i>ARRDC3<\/i> C182Y missense SNP affecting protein function, all other SNPs associated with BCHF are presumed to be linked variants.&nbsp; Likewise, it is also possible that the \n<i>ARRDC3<\/i> C182Y missense SNP is merely linked to a functional variant. &nbsp;To emphasize this point we have modified this sentence towards the end of the first paragraph of the Discussion section:&nbsp; \n<i>Thus, specific DNA sequence variants within ARRDC3 and NFIA are markers for BCHF risk in feedlot cattle in the Western Great Plains, either through linkage to causal variants or direct effects.<\/i>  \n<b>Reviewer 2, point 9:<\/b>&nbsp; In the methods section, the races in the panel of 96 unrelated controls should be mentioned  \n<b>Authors response 9: <\/b>&nbsp;&nbsp;We agree.&nbsp; This information was in our original submission to F1000Research.&nbsp; We have restored this content in the Methods section of the revised article.  \n<b>Reviewer 2, point 10:<\/b> The actual linkage disequilibrium between markers in the two associated genomic regions remains unclear in places. &nbsp;In particular, the question arises whether the SNPs mentioned at the end of the methods section are really located with a LD of 1 to the NFIA variant in intron 4 of the gene.  \n<b>Authors response 10: <\/b>&nbsp;&nbsp;We agree and have rewritten the penultimate paragraph of the article to clarify and discuss the strength of LD between the BCHF-associated SNPs in the two separate genomic regions.&nbsp; With regards to the two best associated \n<i>NFIA<\/i> variants spanning 2.32 kb in intron 4, their LD was high (r\n<sup>2<\/sup> = 0.94).&nbsp; These two SNPs were only moderately linked to a SNP 127 kb upstream in \n<i>NFIA AS2<\/i> (r\n<sup>2<\/sup> = 0.49 and 0.45, Figure S2).  \n<b>Reviewer 2, point 11:<\/b>&nbsp; The wording &quot;homozygous major alleles&quot; on page 10 is unfortunate. Would it not be better to say homozygous for the major allele? An allele itself cannot be homozygous, but the genotype is either hetero- or homozygous for two or one allele.  \n<b>Authors response 11: <\/b>&nbsp;&nbsp;We agree this was terribly worded.&nbsp; The sentence on page 10 line 6 now states, \u201c\n<i>Homozygosity for the major allele of either of these two SNPs was associated with increased BCHF risk (OR 7.4, CI <sub>95<\/sub>, 2.9 to 19, <\/i>\n<i>Table 2<\/i>).\u201d  \n<b>Reviewer 2, point 12:<\/b>&nbsp; In Figure 7 the accession numbers of the listed protein sequences are missing.  \n<b>Authors response 12: <\/b>&nbsp;&nbsp;Figure 7 summarizes the results of a much larger ARRDC3 peptide alignment with 80 accession numbers.&nbsp; We have added this larger alignment with its accession numbers to the extended and underlying data section (Table S2. Extended comparison of ARRDC3 residues near the C182Y position in the Gnathostomes. &nbsp;https:\/\/doi.org\/10.6084\/m9.figshare.22213495  \n<b>Reviewer 2, point 13:<\/b>&nbsp; On page 15, a section on the evaluation of the pathogenicity of the missense variant in the ARRDC3 gene is missing next to the presentation of evolutionary conservation. For example, programs such as MutPred2, SIFT or Provean could be used.  \n<b>Authors response 13: <\/b>&nbsp;&nbsp;We respectfully disagree.&nbsp; As emphasized above in Author response 1, our aim here was not to evaluate the pathogenicity of associated SNPs.&nbsp; In our opinion, such analyses are premature for bead array SNPs, which have a strong selection biased for high minor allele frequencies and represent a only small fraction of the total genetic variation in the region.&nbsp; In silico predictions of&nbsp; pathogenicity of missense variants would be more appropriate once WGS for these regions is available, and the full scope of associated variants is known.&nbsp; However, to increase our understanding of the Y182 variant on the predicted ARRDC3 tertiary structure, we have added alignments from \n<i>de novo<\/i> AlphaFold2 predicted structure in Figure 9 and introduced a hypothesis for testing (Discussion section).  \n<b>Reviewer 2 point 14:<\/b>&nbsp; Table 4 would be easier to understand if actual genotype distributions were listed. Also missing is a clear table on the genotype distribution of the two highlighted markers for the animals from the discovery and confirmation cohorts to clearly assess the results. Table 3 is then a further transformation towards possible practical application, but this original publication should include the true genotypes clearly and legibly.  \n<b>Authors response 14: <\/b>&nbsp;&nbsp;We are happy to provide additional lists of genotypes for figures. &nbsp;We recognize that extracting these genotypes from the provided 770k SNP bead array PLINK file (Supplementary Files S1 through S9) is not trivial. &nbsp;In addition, the revised article now contains genotypes corresponding to&nbsp; the 12 SNPs represented Table 2 for the 204 animals (Table S3), the two SNPs from 566 animals represented in Figure 8 (Table S4), and two SNPs for the 1203 animals listed in Table 4 (Table S5).&nbsp;  We also note that the homozygous \n<i>NFIA<\/i> bar chart data in Figure 8 have changed slightly for the 96 Diversity beef bulls and the 96 persistently infected (BVD) feedlot cattle panels.&nbsp; Their bars increased&nbsp; due to inadvertent initial use of a 3-SNP \n<i>NFIA<\/i> haplotypes instead of just the single \n<i>NFIA<\/i> SNP rs133192205 (ie., BovineHD0300024308 or BCHF32).&nbsp; Since the 3-SNP \n<i>NFIA<\/i> haplotypes were not available for the 171 validation cases, we reverted to using only the single NFIA SNP for all cohorts.  \n<b>Reviewer 2, point 15:<\/b>&nbsp; The second paragraph of the discussion states &quot;an important feature of some BCHF clinical cases...&quot; What exactly does &quot;some&quot; mean here? This should be clarified.  \n<b>Authors response 15: <\/b>&nbsp;&nbsp;We agree.&nbsp; The sentence has been rephased to read: \u201cMore than 50% of the BCHF cases in our study died in the first half of the fattening period.\u201d","URL":"https:\/\/f1000research.com\/articles\/11-385\/v2#referee-comment-11059","order":3,"name":"referee-comment-11059","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.5256\/f1000research.162702.r263441, James Reecy, Department of Animal Science, Iowa State University, Ames, IA, 25 Apr 2024, version 2, indexed","URL":"https:\/\/f1000research.com\/articles\/11-385\/v2#referee-response-263441","order":4,"name":"referee-response-263441","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This research was supported in part by the U.S. Department of\r\nAgriculture, Agricultural Research Service (5438-32000-033-00D, MPH), the University of Nebraska-Lincoln School of Veterinary Medicine and Biomedical Sciences\/Great Plains Veterinary Education Center (DMG, BLV) and the Nebraska Beef Industry Endowment (BLV). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":5,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}