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Common Genetic Variation and Polygenic Disease Risk

Common variation (ie, allele frequency ${>}0.1\%$ ) additionally contributes to the likelihood of a future outcome or the pathogenetic diagnosis of an existing trait or condition. Genome-wide association studies systematically assess for increasing allele frequencies (1) among those with a phenotype of interest versus those without or (2) with increasing severity of a quantitative trait. Because common variation typically occurs outside of highly conserved regions, they are largely in noncoding DNA sequences, each with relatively modest effect sizes for association but providing important clues into disease mechanisms. Genome-wide association studies have been conducted for all common cardiovascular diseases and related traits 21 and have identified significantly associated genomic regions.

Genome-wide association study–associated alleles in aggregate make up PRSs. Cardiovascular PRSs, as covered in a prior American Heart Association scientific statement, 21 represent an opportunity to improve cardiovascular disease prediction, prevention, and management. Because PRSs are established at conception, they have maximal predictive performance earlier in life and for premature events. 22 Despite static genotypes, our interpretations are continually revised; increasingly large and diverse genome-wide association studies and methodological advances are improving PRS performance across populations. 23

A major motivation for participation in DTC-GT is understanding health risks. However, several considerations are required to interpret PRSs from DTC products. First, a DTC PRS product has not yet surmounted FDA clearance or approval, requiring clinical validation. However, physicianordered PRSs are increasingly available, often as LDTs, to enable clinical validation. Second, genotyping technology can influence the performance of PRS. Array-based technologies are primarily used in DTC-GTs and may not fully reflect the diversity of the target population, limiting coverage of relatively important alleles in some populations. Low-coverage whole-genome sequencing, used by some DTC products, may address this issue but typically

requires adequate representation in imputation panels for accurate genotyping. 24 Although deep-coverage wholegenome sequencing resolves these issues, the price point typically is unsuitable for a DTC product, and the incremental gain may be modest for the major ancestral groups. Third, PRS construction and derivation by DTC companies are often opaque, with limited public-facing benchmarking further obscuring interpretation. Fourth, the incorporation of ancestry into PRS reporting remains highly variable. Genetic ancestry is a multidimensional descriptor influencing PRS performance, 25 and self-reported race or ethnicity is an orthogonal health determinant. PRS performance also depends 26 on the importance of other risk factors, competing outcomes, and modifying factors. 25 Variability in PRS reporting across DTC products leads to variable interpretations by patients and clinicians. Ultimately, an integrated risk score conveying absolute risk estimates and incorporating clinical risk factors is desired because genetics should not be considered in isolation. Integrated risk scores are emerging for clinical use. 27

Pharmacogenetic Variation Focusing on Cardiovascular-Related Medications

In addition to DTC-GT to help predict cardiovascular disease risk, DTC pharmacogenetic tests are available to help predict consumers’ responses to some cardiovascular-related medications. Prescribers should be aware that $99\%$ of patients carry at least 1 pharmacogenomic variant, 28 and patients can buy over-the-counter DTC-GTs in many pharmacies. In 2018, 23andMe was the first (and thus far is the only) company to receive marketing authorization from the FDA for DTC testing. The 23andMe DTC pharmacogenomic test, as of this writing, includes 33 variants in 8 genes 29 that apply to several cardiovascular-related medications ( Supplemental Table 1 ). Instructions are available for these DTC pharmacogenomic test results ( Supplemental Table 2 ). 29 Prescribers can find pharmacogenomic clinical practice guidelines from the Clinical Pharmacogenetics Implementation Consortium (https://cpicpgx.org/guidelines) and pharmacogenomic information from the FDA. 30,31 Prescribers should also be aware that as of 2020 the FDA no longer requires confirmatory clinical testing for the 23andMe pharmacogenomic test results for CYP2C19 for 2 specific medications: clopidogrel and citalopram.

In addition to the 23andMe pharmacogenomic test, several other companies are currently offering DTC pharmacogenomic testing that would apply to the cardiovascular-related medications in Supplemental Table 1 through the hybrid or clinician-mediated testing model described previously (eg, Veritas Genetics, Genelex, and Pathway Genomics). Therefore, these pharmacogenomic tests fall under the definition of an LDT and are subject to new increases in FDA oversight. 6 Moreover, many DTC pharmacogenomic tests are advertised for noncardiovascular-related

Table 1. Monogenic Cardiovascular Genes Often Included in Commercial Gene Panel Testing and DTC Tests

|Categories|Conditions| Commonly tested genes| ClinGen definitive and strong evidence*14 | Actionable for condition as perACMG-9415 | |---|---|---|---|---| | Dyslipidemias| Familial hypercholesterolemia|LDLR|义|义| |||APOB|义|| |||PCSK9|义|义| |||LDLRAP1||| ||Other|Biallelic ABCG5||| |||Biallelic ABCG8|X|| |||Biallelic LIPA||| |||BiallelicAPOB||| |Cardiomyopathies|DCM|TNNT2|X|| |Cardiomyopathies||LMNA|X|東X| |Cardiomyopathies||FLNC|X|東X| |Cardiomyopathies||TTN||X| |||BAG3||東X| |||DES||X| |||RBM20||X| |||TNNC1||X| |||SCN5A|义|| |||MYH7||| |||DSP||X| |||PLN||| ||HCM|TNNC1||| |||MYH7||| |||MYBPC3||| |||TNNI3||| |||TPM1||| |||MYL3||| |||ACTC1||| |||PRKAG2||| |||MYL2|X|| |||TNNT2||| |||ALPK3||| ||ARVC|PKP2||义| |||DSP||义| |||D:SC2||| |||TMEM43||| |||DSG2||| |||JUP|XIT|| || Hereditary ATTR amyloidosis |TTR||义| || Fabry disease|GLA|义|义| || Pompe disease|GAA|义|义| ||Hereditary hemochromatosis|HFE|义|义| | Inherited arrhythmias|Familial AF#|SCN5A||| |||KCNQ1||| |||MYL4||| |||TTN|||

Table 1. Continued

|Categories|Conditions|Commonly tested genes| ClinGen definitive and strong evidence*14 | Actionable for condition as per ACMG-9415 | |---|---|---|---|---| ||LOTS|KCNO1|义|| |||KCNH2||| |||SCN5A|义|| |||CALM1||東X| |||CALM2|义|义| |||CALM3||| |||TRDN|义|| ||BrS|SCN5A||| ||CPVT|RYR2||X| |||CASO2||| |||TRDN|义|| |||TECRL||| |||CALM1|XIT|| |||TRDN||| | Thoracic aortic disease | Marfan syndrome|FBN1|义|| ||LDS|TGFBR1|X|| |||TGFBR2||| |||TGFB2|X|| |||TGFB3||| |||SMAD3|义|义| ||nsHTAD|ACTA2|X|X| |||MYH11||义| |||PRKG1|X|| |||MYLK|义|| ||EDS (vascular)|COL3A1|义||

ACMG indicates American College of Medical Genetics and Genomics; AF, atrial fibrillation; ARVC, arrhythmogenic right ventricular cardiomyopathy; ATTR, transthyretin amyloidosis; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; DTC, direct-to-consumer; EDS, Ehlers-Danlos syndrome; HCM, hypertrophic cardiomyopathy; LDS, Loeys-Dietz syndrome; LQTS, long QT syndrome; nsHTAD, nonsyndromic heritable thoracic aortic disease; and RCM, restrictive cardiomyopathy. ClinGen systematic classification of gene-disease relationships is included for those considered definitive and strong evidence at the time of writing. 14 Some of these are considered actionable by “ACMG SF v3.2 List for Reporting of Secondary Findings in Clinical Exome and Genome Sequencing.” 15 \*ClinGen curation is most accurate on the website and may not yet be published. †Definitive and strong evidence in pediatric populations. ‡Familial AF has not been curated by ClinGen; AF was previously categorized as a Class 3 (do not do) for genetic testing and is now Class 2 (consider) per most recent expert consensus statement. 16

medications such as those for treating mental health conditions (eg, ClarityX and Tempus), but the results for many of the same genes and variants would also affect cardiovascular-related medications (eg, CYP2C19 ). Several third-party companies will also translate raw genetic data from DTC-GTs into pharmacogenomic results.

paramount. The ACCE framework ( Supplemental Table 3 ) has been widely adopted as a guiding framework and comprises a series of 44 questions to assess the analytical validity, clinical validity, clinical utility, and associated ethical, legal, and social issues for GT. 32 Analytical validity relates to technical sensitivity and specificity for accurate genotyping. Similarly, clinical validity involves determining the sensitivity and specificity of the test for the clinical condition. Clinical utility relates to how well a test can lead to the prevention of or better treatment for a genetic condition.

CONTEXTUALIZING THE POTENTIAL RISKS AND BENEFITS OF DTC-GT WITH THE ACCE FRAMEWORK

Given the substantial variation in DTC-GT and documentation available about these tests, a clinical framework for evaluating the DTC-GT under consideration is

Only a handful of DTC-GTs are FDA approved and thus have gone through a process to demonstrate analytical and clinical validity. 10 DTC-GTs usually will not definitively indicate that a disease will develop or exclude

that it will not develop. A false-positive test may lead to unnecessary diagnostic procedures or therapies. Conversely, DTC-GTs often do not test for all genetic variants for a specific condition and could provide false reassurance and result in the foregoing of evidence-based preventive, diagnostic, or therapeutic options. 1

In terms of the clinical utility of DTC-GT, among the major benefits touted for DTC-GTs is empowering individuals for proactive personalized health management and satisfying curiosity about genetic ancestry. However, studies supporting the effects of DTC-GTs on behavioral changes or attendance at screening or support programs have been variable. 33 “Gene-first” screening strategies for Centers for Disease Control and Prevention Tier 1 conditions, which include familial hypercholesterolemia, are likely to be cost-effective in US adults ${\le}50$ years of age. 34 Similarly neonatal gene-first screening for hypertrophic cardiomyopathy may translate to saved lives but with high surveillance costs because of variable penetrance. 35

Last, there are substantial considerations regarding the ethical, legal, and social implications of DTC-GT. Although there are some potential benefits, including increased consumer autonomy and ease of accessing genetic health information (Figure1 and Supplemental Table 3 ), major concerns include the lack of genetic counseling, misinterpretation of the value of results, and risk for loss of data privacy. 36 The Genetic Information Nondiscrimination Act of 2008 protects against discrimination in employment and health insurance coverage based on genetic information, including DTCGT, but not “luxury” insurance such as life, disability, or long-term care insurance. DTC-GTs companies are not covered by the Health Information Portability and Accountability Act of 1996, and GT companies may have consent forms that provide them with rights to the DNA information that can be shared for research or publicly. 37 Positive DTC-GT results can burden health care systems if patients seek follow-up from their clinical team. Conversely, the inability to access clinical care after DTC-GT can also be of concern. Last, a clearer delineation of medicolegal liability related to DTC-GT in clinical care is needed. 38

SPECIAL POPULATION CONSIDERATIONS

DTC-GTs may have different risk/benefit profiles depending on the consumer population.

Athletes

Sports cardiologists should be aware of DTC-GT companies marketing identification of genetic factors to guide performance prediction, injury prevention, and athletetailored specific training. 39,40 The leading example of

genotype-informed training is testing for sickle cell trait. An association between sickle cell trait and an increased risk of death attributable to exertional rhabdomyolysis without appropriate hydration and training modification was observed historically in athletes and army recruits. Despite a lack of clinical evidence to support testing athletes for sickle cell trait, in 2010, after the settlement of a lawsuit brought by the family of a 19-year-old freshman at Rice University with sickle cell trait who died after football practice, the National Collegiate Athletic Association approved mandatory testing for all Division I sports athletes. 41

However, the current literature does not support the genotyping of athletes. Although studies in elite athletes suggest that target genes may confer athletic phenotype advantages or disadvantages, 42 small sample sizes, biased methodologies, and complex athletic phenotypes limit the actionability of associations identified to date and pose challenges that must be overcome in future investigations. 43 The prevailing consensus is that DTCGTs should not play a role in identifying potential elite athletes or in training optimization. 40,44

Despite this, multiple DTC companies have emerged that advertise GT to identify athletic prowess, to enhance performance, and to prevent injuries. 44 Legislation in several countries is hamstrung because it does not address companies that offer the service but refrain from giving advice. 45 A growing issue pertains to companies offering integration of personal genetics with fitness tracking data, directing nutritional and exercise regimens. This strategy is marred by significant risks to privacy, poor-quality recommendations lacking scientific basis, and limited benefit of the information offered. 46 Several important factors limit and caution against the widespread use of DTCGTs in sports, so further studies are needed to generate evidence-based guidance to improve athletes’ performance and safety.

Adoptees and Individuals With Limited Family Health History Knowledge

DTC-GT can provide genetic information to adoptees and individuals who may have limited ability to learn about their family health history (ie, if estranged from relatives or biological relatives are deceased) because an unknown family health history and parentage is not currently an indication for clinical GT. For such individuals, the limitations of testing should be made clear; in addition, adoptees may benefit from discussing the possibility that DTC-GT may uncover distant relatives, and the results may affect the health of relatives and biological children. Involving genetics professionals such as genetic counselors (GCs) may be helpful. Positive DTC-GT results should be clinically confirmed to determine the next steps in management.

Aging Populations

DTC-GT presents a unique opportunity for aging populations, particularly for those interested in longevity genes and the risk of late-onset diseases. 47 Older adults may be drawn to testing to explore potential longevity genes such as ${\cal F O X O3},$ which is associated with aging and DNA repair, 48 and APOE genotyping for Alzheimer disease risk, which also is implicated in lipid metabolism. 49 Although DTC-GTs offer potential insights into longevity, they also pose challenges such as the risk of misinterpretation of complex genetic information without professional counseling.

Limited-Resource Communities

DTC-GT companies targeting affluent consumers may exacerbate inequities in GT access for lower socioeconomic groups. 50 Affordability may limit access because insurance will not cover these tests. Inadequate access to requisite technology, including smart devices, computers, and broadband, can limit participation in DTC testing because many companies rely on digital signup and electronic consent platforms. If consumers use DTC-GT in resource-limited settings, keen attention should be paid to the quality and credibility of the DTC company and to patient access to health care resources, including genetic counseling and specialty services, data privacy, and the potential misuse of genetic information. 2 DTC-GT should not replace traditional screening and diagnostic methods for health risks.

CLINICAL CONSIDERATIONS WHEN CONFRONTING DTC-GT RESULTS

Figure2 presents an approach that may be used by clinicians presented with DTC-GT results. Beyond eliciting the patient’s reasons for pursuing the DTC-GT, the clinician may find that a systematic review of the test report may be helpful.

Reviewing the Test Report

The largest resource for arbitrating the clinical evidence and relevance of genetic variants is ClinGen. 51 This consortium of experts works closely with the American College of Medical Genetics and Genomics and the FDA to standardize variant curation and public-facing evidence representation. The ClinGen consortium’s expert panels aim to provide the most up-to-date and disease-specific variant curation guidelines; such panels exist for various cardiomyopathies, arrhythmias, aortopathies, and dyslipidemias. The FDA has adopted ClinGen assertions about genetic variant pathogenicity as belonging to an “FDArecognized database.” 52 These assertions are viewable in ClinVar, a public repository of genetic variants in which laboratories can publish their evidence reviews. 52

Clinicians should be able to obtain the evidence curation protocols from DTC companies and determine whether they have adopted expert standards. Variants identified by DTC companies can also be queried with ClinVar to understand the level of evidence review available for these variants. Last, ClinGen provides guidance for laboratories concerning data sharing and transparency as a quality assurance measure, about which clinicians may also inquire. 52

Facilitating Subsequent Patient Care Needs

Engaging Genetic Counselors as Members of the Care Team

Engaging a GC’s help as a member of the clinical care team may be useful when confronted with DTC-GT–related questions or results. Licensed GCs have at least a master’s degree in genetics or a related field. Although GCs can obtain and evaluate patient and family medical histories; counsel, consent, and guide the test-ordering process for GT; and communicate results to patients and their families, 53 there are some limitations to the scope of practice of GCs. GCs are unable to diagnose medical conditions or to prescribe treatment. Variations in state laws lead to inconsistencies in GCs’ ability to order GT independently compared with under the supervision of an authorized clinician.

Consumers engaging in DTC-GT may be able to access genetic counseling through 3 different avenues. First, patients may bring their DTC-GT results to their clinician to discuss the results or be referred to a GC or other specialist, although many clinicians may lack adequate training or comfort in interpreting these results. Second, many DTC companies offer telehealth genetic counseling services to consumers, 54 although there is no standard scope of practice for these services, and services offered may vary widely. Third, independent telehealth genetic counseling companies may be an option for those seeking additional education, assessment, and confirmatory clinical GT in instances when patients cannot access genetic counseling services at their health care institution or through the DTC-GT company. 54 Care coordination and follow-up may be challenging for options outside the health care system.

Nonactionable Results

One point of tension in the DTC-GT industry is that patients may still bring their DTC-GT results to their physicians, 55 regardless of whether this is clinically necessary. However, unless indicated by additional personal or family medical history or phenotypic features, patients with test results that do not contain health risk information or indicate a low risk of complex disease, those who do not have pharmacogenetic test results of relevance to them, or those with tests that are negative for variants implicated in monogenic disease do not necessarily need further follow-up. 36 The reason is that monogenic cardiovascular

 Figure 2. An approach to the management of DTC-GT results. ACCE indicates analytical validity, clinical validity, clinical utility, and associated ethical, legal and social implications; AHA, American Heart Association; DTC-GT, direct-to-consumer genetic testing; FDA, US Food and Drug Administration; and PRS, polygenic risk score. \* Additional considerations may be found in the AHA statement on polygenic risk scores. 21

disease is uncommon in the population, so DTC-GT users without prior known risk of disease will overwhelmingly receive nonactionable monogenic results. Typically, DTC companies will not report uncertain results.

Confirmation of Potentially Actionable Results

Patients with potentially actionable DTC results are typically encouraged to follow up with a GC or other qualified clinician for subsequent assessment and coordination of care needs. Some DTC companies may also allow customers to download raw genotyping data, including potentially actionable variants. In almost all cases, confirmatory clinical testing is recommended for any health-related monogenic DTC-GT results because of concerns about limited assay coverage and accuracy, including false positives, 56 and consumers must discuss their DTC-GT results with a clinician before adjusting any therapy. 57 DTC-GTs usually do not capture all pathogenic or potentially pathogenic variants because they are usually performed with SNP-genotyping arrays instead of deep-coverage sequencing.

Management of Actionable DTC-GT Results

Management of actionable DTC-GT results will depend on the specific result and a correlation with the patient’s

history, medications, and clinical findings (Figure2 and Table2). Qualified clinicians within the health care system can assess the legitimacy of DTC results through confirmatory GT or clinical and family history assessment.

Declined Confirmatory Testing of DTC-GT Results

In instances in which patients decline confirmatory testing, GCs and other members of the health care team should assess whether a patient has a suspected increased risk for inherited cardiovascular disease based on multiple data sources, including the DTC result, patient’s clinical history, and family history. If there is concern for disease risk, a referral to a cardiovascular specialist is warranted.

Cascade Testing for Family Members

Cascade testing involves informing relatives about genetic conditions within a family and encouraging them to undergo targeted testing for early prevention or treatment. 58 However, the adoption rate for cascade GT in traditional clinical genetics workflows is ${<}50\%$ , hindered by various challenges; the specific frequency of cascade testing for DTC-GTs remains uncertain. 59 DTC-GT companies generally do not actively facilitate

Table 2. Clinical Evaluation for Carriers of Disease-Causing Variants With DTC Testing to Determine Clinical Actionability

| History and physical examination with particular attention to signs and symptoms of disease of interest | |---| | 3-Generation family history| |Confirmation of monogenic results with CLIA-certified retesting if necessary| |Consider cascade testing if indicated for family members| |If confirmed, additional disease-specific testing may include the following:| |Laboratory testing (eg,lipid panel)| |Electrocardiogram| |Exercise treadmill testing| |Cardiac imaging (eg, TTE, MR, or PET)| |Vascular imaging (eg, TTE, CTA, or MRA)| |Surveillance imaging| |Cascade genetic testing with genetic counselling| |Specialist referral as needed|

Table contents informed by multiple data sources. 18–20 CLIA indicates Clinical Laboratory Improvement Amendments; CTA, computed tomography angiography; DTC, direct-to-consumer; MR, magnetic resonance; MRA, magnetic resonance angiography; PET, positron emission tomography; and TTE, transthoracic echocardiography.

cascade testing. Cascade testing is not strongly indicated for DTC-GT results not inherited in a mendelian fashion such as PRSs; however, consideration of cascade testing may still be warranted given the high concordance between relatives with high PRS for complex disease. 60

There are no current guidelines on approaching family members for cascade screening after DTC-GT. This raises issues amid the growing use of DTC-GT, especially considering that inaccuracies such as misclassified variants may lead to stress, unnecessary medical procedures, and financial burdens for both the consumer and, if shared with others, family members. Studies show mixed results on whether clinicians should notify relatives of patients with potentially actionable DTC-GT results with the patient’s consent. 61 Family communication about hereditary conditions may be sensitive. Talking to children about hereditary conditions requires a considerate approach tailored to their age and concerns. Therefore, consumer guidelines on cascade testing from DTC-GT are necessary to facilitate the disclosure of genetic information to family members. 54

CONCLUSIONS

The expansive, heterogenous DTC-GT market may democratize access to genetic information for patients. Despite insufficient evidence to support the use of DTC-GT in routine clinical care, cardiovascular patients may present DTC-GT results to health care professionals. However, limited oversight and regulation, variability in scope

and testing methods, and a lack of standardized systems for reporting and counseling consumers about results may generate confusion about DTC-GT for patients and clinicians alike. Frameworks such as the ACCE provide structure in the evaluation of test quality, but protocols for managing DTC-GT results are needed. We present a general approach to managing DTC-GT for cardiovascular health risks.

Future work should focus on developing standards for the DTC-GT industry. These should include standards for information delivery to consumers before and after testing; clear guidelines for using DTC results clinically, including recommended confirmation of initial tests and notification procedures for familial testing; and enacting of safeguards to protect patients, clinicians, and health care systems from possible negative downstream outcomes from DTC-GT. In addition, cardiovascular and genetics specialists must consider how to facilitate greater traditional clinical genetics access or be prepared to accommodate ever-increasing processing of external DTC-GT results to meet the evolving needs of our patients.

ARTICLE INFORMATION

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on November 26, 2024, and the American Heart Association Executive Committee on January 16, 2025. A copy of the document is available at https://professional.heart.org/statements by using either “Search for Guidelines & Statements” or the “Browse by Topic” area. To purchase additional reprints, call 215-356-2721 or email Meredith. Edelman@wolterskluwer.com

The American Heart Association requests that this document be cited as follows: Hull LE, Aday AW, Bui QM, Luzum JA, Muchira JM, Wand H, Chahal CAA, Chung MK, Kwitek AE, Molossi S, Natarajan P; on behalf of the American Heart Association Data Science and Precision Medicine Committee of the Council on Genomic and Precision Medicine and Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Lifestyle and Cardiometabolic Health; and Council on Peripheral Vascular Disease. Direct-toconsumer genetic testing for cardiovascular disease: a scientific statement from the American Heart Association. Circulation . 2025;151:e•••–e•••. doi: 10.1161/ CIR.0000000000001304

The expert peer review of AHA-commissioned documents (eg, scientific statements, clinical practice guidelines, systematic reviews) is conducted by the AHA Office of Science Operations. For more on AHA statements and guidelines development, visit https://professional.heart.org/statements. Select the “Guidelines & Statements” drop-down menu, then click “Publication Development.”

Permissions: Multiple copies, modification, alteration, enhancement, and distribution of this document are not permitted without the express permission of the American Heart Association. Instructions for obtaining permission are located at https://www.heart.org/permissions. A link to the “Copyright Permissions Request Form” appears in the second paragraph (https://www.heart.org/en/about-us/ statements-and-policies/copyright-request-form).

Acknowledgments

Isabella Volkers, an undergraduate student at the University of Michigan, assisted with the literature search and summary and initial drafts related to the following topics: LDTs, pharmacogenetics, and confirmatory testing.

Disclosures

Writing Group Disclosures

| Writing group member |Employment|Research grant| Other research support | Speakers' bureau/ honoraria | Expert witness | Ownership interest |Consultant/advisory board|Other| |---|---|---|---|---|---|---|---|---| | Leland E. Hull | Massachu- setts General Hospital, Cardiovascu- lar Research Center | NIH (NHGRI K08HG01221)t; Cystic Fibrosis Foundation (006233A133)+ |None|None|None|None|None|None| | Pradeep Natarajan | Massachu- setts General Hospital Cardiovascu- lar Research Center | Allelica*; Novartis*; Genentech/ Roche*;NIHt; Manton Foundationt (all investigator- initiated research) ||None|None| Bolt*;Can- dela*; Mercury*; MyOme*; Pa- rameter Health*; TenSixteen Bio*; Preciseli*; Vertex Pharmaceuticalst | Allelica*; Blackstone Life Sciences*; CRISPR Therapeu- tics*; Eli Lily Co*; HeartfFlow*; Magnet Biomedicine*; Esperion Therapeutics*; Merck*; GV*; Genentech/Roche*; Novartis*; TenSixteen Bio*; Foresite Capital*; Foresite Labs*; Tourmaine Bio* | Vertex Pharma- ceuticals (immediate family members, senior medi- cal director)+ | | Aaronw. Aday | Vanderbilt University Medical Center |None|None|None|None|None|None|None| | Quan M. Bui | UCSan Diego | AHA(AHA Career Develop- ment Award)t; lonis (Janice Weisman Young Investigator Grant)+ |None|None|None|None| Lexeo Therapeutics (unpaid)*; CardioGenomic Testing Alliance (unpaid)* |None| | C.Anwar A. Chahal | Mayo Clinic College of Medicine |None|None|None|None|None|None|None| | Mina K. Chung | Cleveland Clinic |None|None|None|None|None|None|None| | AnneE. Kwitek | Medical College of Wisconsin | NIH (research funding from NHLBI, OD, NHGRI)+ | Advancing aHealthier Wisconsint |None|None|None|None|None| | Jasmine A. Luzum | University of Michigan College of Pharmacy AnnArbor | NIH (K08 HL146990)+ |None|None|None|None|Ariel Precision Medicine*|None| | Silvana Molossi | Texas Children's Hospital/ Baylor College of Medicine |None|None|None|None|None|None|None| | James M. Muchira | Vanderbilt University |None|None|None|None|None|None|None| | Hannah wand | Stanford Health Care |None|None|None|None|None|None|None|

This table represents the relationships of writing group members that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all members of the writing group are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $\S5000$ or more during any 12-month period, or $5\%$ or more of the person’s gross income; or (b) the person owns $5\%$ or more of the voting stock or share of the entity, or owns $\S5000$ or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. \*Modest.

†Significant.

Reviewer Disclosures

|Reviewer|Employment| Research grant | Other research support | Speakers' bureau/ honoraria | Expert witness |Ownership interest| Consultant/ advisory board |Other| |---|---|---|---|---|---|---|---|---| |Emily Brown| Johns Hopkins University|None|None|None|None|None|None|None| |Melanie Care| University Health Network and Mount Sinai Hospital (Canada) |None|None|None|None|None|None|None| |Wendy K. Chung| Columbia University School of Medicine |None|None|None|None|None|None|None| |Renato Polimanti| Yale University School of Medicine | Alkermes (research grant)t |None|None|None|None| Karger Publishers* |None| |Matthew Thomas|University of Virginia|None|None|None|None|Genome Medical, Inc*|None|None|

This table represents the relationships of reviewers that may be perceived as actual or reasonably perceived conflicts of interest as reported on the Disclosure Questionnaire, which all reviewers are required to complete and submit. A relationship is considered to be “significant” if (a) the person receives $\S5000$ or more during any 12-month period, or $5\%$ or more of the person’s gross income; or (b) the person owns $5\%$ or more of the voting stock or share of the entity, or owns $\S5000$ or more of the fair market value of the entity. A relationship is considered to be “modest” if it is less than “significant” under the preceding definition. \*Modest.

†Significant.

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