@article {127, title = {Rapid response to the alpha-1 adrenergic agent phenylephrine in the perioperative period is impacted by genomics and ancestry.}, journal = {Pharmacogenomics J}, volume = {21}, year = {2021}, month = {2021 Apr}, pages = {174-189}, abstract = {

The emergence of genomic data in biobanks and health systems offers new ways to derive medically important phenotypes, including acute phenotypes occurring during inpatient clinical care. Here we study the genetic underpinnings of the rapid response to phenylephrine, an α1-adrenergic receptor agonist commonly used to treat hypotension during anesthesia and surgery. We quantified this response by extracting blood pressure (BP) measurements 5 min before and after the administration of phenylephrine. Based on this derived phenotype, we show that systematic differences exist between self-reported ancestry groups: European-Americans (EA; n = 1387) have a significantly higher systolic response to phenylephrine than African-Americans (AA; n = 1217) and Hispanic/Latinos (HA; n = 1713) (31.3\% increase, p value < 6e-08 and 22.9\% increase, p value < 5e-05 respectively), after adjusting for genetic ancestry, demographics, and relevant clinical covariates. We performed a genome-wide association study to investigate genetic factors underlying individual differences in this derived phenotype. We discovered genome-wide significant association signals in loci and genes previously associated with BP measured in ambulatory settings, and a general enrichment of association in these genes. Finally, we discovered two low frequency variants, present at ~1\% in EAs and AAs, respectively, where patients carrying one copy of these variants show no phenylephrine response. This work demonstrates our ability to derive a quantitative phenotype suited for comparative statistics and genome-wide association studies from dense clinical and physiological measures captured for managing patients during surgery. We identify genetic variants underlying non response to phenylephrine, with implications for preemptive pharmacogenomic screening to improve safety during surgery.

}, issn = {1473-1150}, doi = {10.1038/s41397-020-00194-5}, author = {Wenric, Stephane and Jeff, Janina M and Joseph, Thomas and Yee, Muh-Ching and Belbin, Gillian M and Owusu Obeng, Aniwaa and Ellis, Stephen B and Bottinger, Erwin P and Gottesman, Omri and Levin, Matthew A and Kenny, Eimear E} } @article {85, title = {A brief history of human disease genetics.}, journal = {Nature}, volume = {577}, year = {2020}, month = {2020 01}, pages = {179-189}, abstract = {

A primary goal of human genetics is to identify DNA sequence variants that influence biomedical traits, particularly those related to the onset and progression of human disease. Over the past 25 years, progress in realizing this objective has been transformed by advances in technology, foundational genomic resources and analytical tools, and by access to vast amounts of genotype and phenotype data. Genetic discoveries have substantially improved~our understanding of the mechanisms responsible for many rare and common diseases and driven development of novel preventative and therapeutic strategies. Medical innovation will increasingly focus on delivering care tailored to individual patterns of genetic predisposition.

}, keywords = {Animals, Genetic Testing, Genetic Variation, Genomics, Genotype, Humans, Phenotype, Rare Diseases}, issn = {1476-4687}, doi = {10.1038/s41586-019-1879-7}, author = {Claussnitzer, Melina and Cho, Judy H and Collins, Rory and Cox, Nancy J and Dermitzakis, Emmanouil T and Hurles, Matthew E and Kathiresan, Sekar and Kenny, Eimear E and Lindgren, Cecilia M and MacArthur, Daniel G and North, Kathryn N and Plon, Sharon E and Rehm, Heidi L and Risch, Neil and Rotimi, Charles N and Shendure, Jay and Soranzo, Nicole and McCarthy, Mark I} } @article {126, title = {A common variant in PNPLA3 is associated with age at diagnosis of NAFLD in patients from a multi-ethnic biobank.}, journal = {J Hepatol}, volume = {72}, year = {2020}, month = {2020 06}, pages = {1070-1081}, abstract = {

BACKGROUND \& AIMS: The Ile138Met variant (rs738409) in the PNPLA3 gene has the largest effect on non-alcoholic fatty liver disease (NAFLD), increasing the risk of progression to severe forms of liver disease. It remains unknown if the variant plays a role in age of NAFLD onset. We aimed to determine if rs738409 impacts on the age of NAFLD diagnosis.

METHODS: We applied a novel natural language processing (NLP) algorithm to a longitudinal electronic health records (EHR) dataset of >27,000 individuals with genetic data from a multi-ethnic biobank, defining NAFLD cases (n~= 1,703) and confirming controls (n~= 8,119). We conducted i) a survival analysis to determine if age at diagnosis differed by rs738409 genotype, ii) a receiver operating characteristics analysis to assess the utility of the rs738409 genotype in discriminating NAFLD cases from controls, and iii) a phenome-wide association study (PheWAS) between rs738409 and 10,095 EHR-derived disease diagnoses.

RESULTS: The PNPLA3 G risk allele was associated with: i) earlier age of NAFLD diagnosis, with the strongest effect in Hispanics (hazard ratio 1.33; 95\% CI 1.15-1.53; p <0.0001) among whom a NAFLD diagnosis was 15\% more likely in risk allele carriers vs. non-carriers; ii) increased NAFLD risk (odds ratio 1.61; 95\% CI 1.349-1.73; p <0.0001), with the strongest effect among Hispanics (odds ratio 1.43; 95\% CI 1.28-1.59; p <0.0001); iii) additional liver diseases in a PheWAS (p <4.95~{\texttimes} 10) where the risk variant also associated with earlier age of diagnosis.

CONCLUSION: Given the role of the rs738409 in NAFLD diagnosis age, our results suggest that stratifying risk within populations known to have an enhanced risk of liver disease, such as Hispanic carriers of the rs738409 variant, would be effective in earlier identification of those who would benefit most from early NAFLD prevention and treatment strategies.

LAY SUMMARY: Despite clear associations between the PNPLA3 rs738409 variant and elevated risk of progression from non-alcoholic fatty liver disease (NAFLD) to more severe forms of liver disease, it remains unknown if PNPLA3 rs738409 plays a role in the age of NAFLD onset. Herein, we found that this risk variant is associated with an earlier age of NAFLD and other liver disease diagnoses; an observation most pronounced in Hispanic Americans. We conclude that PNPLA3 rs738409 could be used to better understand liver disease risk within vulnerable populations and identify patients that may benefit from early prevention strategies.

}, issn = {1600-0641}, doi = {10.1016/j.jhep.2020.01.029}, author = {Walker, Ryan W and Belbin, Gillian M and Sorokin, Elena P and Van Vleck, Tielman and Wojcik, Genevieve L and Moscati, Arden and Gignoux, Christopher R and Cho, Judy and Abul-Husn, Noura S and Nadkarni, Girish and Kenny, Eimear E and Loos, Ruth J F} } @article {122, title = {Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations.}, journal = {Am J Hum Genet}, volume = {107}, year = {2020}, month = {2020 10 01}, pages = {788-789}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2020.08.020}, author = {Martin, Alicia R and Gignoux, Christopher R and Walters, Raymond K and Wojcik, Genevieve L and Neale, Benjamin M and Gravel, Simon and Daly, Mark J and Bustamante, Carlos D and Kenny, Eimear E} } @article {103, title = {Multi-Ethnic Genome-Wide Association Study of Decomposed Cardioelectric Phenotypes Illustrates Strategies to Identify and Characterize Evidence of Shared Genetic Effects for Complex Traits.}, journal = {Circ Genom Precis Med}, volume = {13}, year = {2020}, month = {2020 08}, pages = {e002680}, abstract = {

BACKGROUND: We examined how expanding electrocardiographic trait genome-wide association studies to include ancestrally diverse populations, prioritize more precise phenotypic measures, and evaluate evidence for shared genetic effects enabled the detection and characterization of loci.

METHODS: We decomposed 10 seconds, 12-lead electrocardiograms from 34 668 multi-ethnic participants (15\% Black; 30\% Hispanic/Latino) into 6 contiguous, physiologically distinct (P wave, PR segment, QRS interval, ST segment, T wave, and TP segment) and 2 composite, conventional (PR interval and QT interval) interval scale traits and conducted multivariable-adjusted, trait-specific univariate genome-wide association studies using 1000-G imputed single-nucleotide polymorphisms. Evidence of shared genetic effects was evaluated by aggregating meta-analyzed univariate results across the 6 continuous electrocardiographic traits using the combined phenotype adaptive sum of powered scores test.

RESULTS: We identified 6 novels (, and ) and 87 known loci (adaptive sum of powered score test <5{\texttimes}10). Lead single-nucleotide polymorphism rs3211938 at was common in Blacks (minor allele frequency=10\%), near monomorphic in European Americans, and had effects on the QT interval and TP segment that ranked among the largest reported to date for common variants. The other 5 novel loci were observed when evaluating the contiguous but not the composite electrocardiographic traits. Combined phenotype testing did not identify novel electrocardiographic loci unapparent using traditional univariate approaches, although this approach did assist with the characterization of known loci.

CONCLUSIONS: Despite including one-third as many participants as published electrocardiographic trait genome-wide association studies, our study identified 6 novel loci, emphasizing the importance of ancestral diversity and phenotype resolution in this era of ever-growing genome-wide association studies.

}, issn = {2574-8300}, doi = {10.1161/CIRCGEN.119.002680}, author = {Baldassari, Antoine R and Sitlani, Colleen M and Highland, Heather M and Arking, Dan E and Buyske, Steve and Darbar, Dawood and Gondalia, Rahul and Graff, Misa and Guo, Xiuqing and Heckbert, Susan R and Hindorff, Lucia A and Hodonsky, Chani J and Ida Chen, Yii-Der and Kaplan, Robert C and Peters, Ulrike and Post, Wendy and Reiner, Alex P and Rotter, Jerome I and Shohet, Ralph V and Seyerle, Amanda A and Sotoodehnia, Nona and Tao, Ran and Taylor, Kent D and Wojcik, Genevieve L and Yao, Jie and Kenny, Eimear E and Lin, Henry J and Soliman, Elsayed Z and Whitsel, Eric A and North, Kari E and Kooperberg, Charles and Avery, Christy L} } @article {89, title = {A positively selected FBN1 missense variant reduces height in Peruvian individuals.}, journal = {Nature}, volume = {582}, year = {2020}, month = {2020 06}, pages = {234-239}, abstract = {

On average, Peruvian individuals are among the shortest in the world. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7\%) reduces height by 2.2~cm (4.4~cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin~1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

}, keywords = {Body Height, Female, Fibrillin-1, Gene Frequency, Genome-Wide Association Study, Heredity, Humans, Indians, South American, Male, Microfibrils, Mutation, Missense, Peru, Selection, Genetic}, issn = {1476-4687}, doi = {10.1038/s41586-020-2302-0}, author = {Asgari, Samira and Luo, Yang and Akbari, Ali and Belbin, Gillian M and Li, Xinyi and Harris, Daniel N and Selig, Martin and Bartell, Eric and Calderon, Roger and Slowikowski, Kamil and Contreras, Carmen and Yataco, Rosa and Galea, Jerome T and Jimenez, Judith and Coit, Julia M and Farro{\~n}ay, Chandel and Nazarian, Rosalynn M and O{\textquoteright}Connor, Timothy D and Dietz, Harry C and Hirschhorn, Joel N and Guio, Heinner and Lecca, Leonid and Kenny, Eimear E and Freeman, Esther E and Murray, Megan B and Raychaudhuri, Soumya} } @article {73, title = {Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank.}, journal = {Genome Med}, volume = {12}, year = {2019}, month = {2019 Dec 31}, pages = {2}, abstract = {

BACKGROUND: Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City.

METHODS: Exome sequence data from 30,223 adult BioMe participants were evaluated for pathogenic variants in BRCA1/2. Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals.

RESULTS: There were 218 (0.7\%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other~Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4\%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28\% of variant-positive individuals had a personal history, and 45\% had a personal or family history of BRCA1/2-associated cancers. Approximately 27\% of variant-positive individuals had prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (39\%) than those with other pathogenic variants (20\%).

CONCLUSIONS: These findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.

}, issn = {1756-994X}, doi = {10.1186/s13073-019-0691-1}, author = {Abul-Husn, Noura S and Soper, Emily R and Odgis, Jacqueline A and Cullina, Sinead and Bobo, Dean and Moscati, Arden and Rodriguez, Jessica E and Loos, Ruth J F and Cho, Judy H and Belbin, Gillian M and Suckiel, Sabrina A and Kenny, Eimear E} } @article {58, title = {Personalized Medicine and the Power of Electronic Health Records.}, journal = {Cell}, volume = {177}, year = {2019}, month = {2019 Mar 21}, pages = {58-69}, abstract = {

Personalized medicine has largely been enabled by the integration of genomic and other data with electronic health records (EHRs) in the United States and elsewhere. Increased EHR adoption across various clinical settings and the establishment of EHR-linked population-based biobanks provide unprecedented opportunities for the types of translational and implementation research that drive personalized medicine. We review advances in the digitization of health information and the proliferation of genomic research in health systems and provide insights into emerging paths for the widespread implementation of personalized medicine.

}, issn = {1097-4172}, doi = {10.1016/j.cell.2019.02.039}, author = {Abul-Husn, Noura S and Kenny, Eimear E} } @article {61, title = {Genetic diversity in populations across Latin America: implications for population and medical genetic studies.}, journal = {Curr Opin Genet Dev}, volume = {53}, year = {2018}, month = {2018 12}, pages = {98-104}, abstract = {

Hispanic/Latino (H/L) populations, although linked by culture and aspects of shared history, reflect the complexity of history and migration influencing the Americas. The original settlement by indigenous Americans, followed by postcolonial admixture from multiple continents, has yielded localized genetic patterns. In addition, numerous H/L populations appear to have signatures of pre-colonization and post-colonization bottlenecks, indicating that tens of millions of H/Ls may harbor signatures of founder effects today. Based on both population and medical genetic findings we highlight the extreme differentiation across the Americas, providing evidence for why H/Ls should not be considered a single population in modern human genetics. We highlight the need for additional sampling of understudied H/L groups, and ramifications of these findings for genomic medicine in one-tenth of the world{\textquoteright}s population.

}, keywords = {African Continental Ancestry Group, European Continental Ancestry Group, Genetic Variation, Genetics, Medical, Genetics, Population, Genome, Human, Genomics, Humans, Latin America}, issn = {1879-0380}, doi = {10.1016/j.gde.2018.07.006}, author = {Belbin, Gillian M and Nieves-Col{\'o}n, Maria A and Kenny, Eimear E and Moreno-Estrada, Andres and Gignoux, Christopher R} } @article {39, title = {Imputation-Aware Tag SNP Selection To Improve Power for Large-Scale, Multi-ethnic Association Studies.}, journal = {G3 (Bethesda)}, volume = {8}, year = {2018}, month = {2018 Oct 03}, pages = {3255-3267}, abstract = {

The emergence of very large cohorts in genomic research has facilitated a focus on genotype-imputation strategies to power rare variant association. These strategies have benefited from improvements in imputation methods and association tests, however little attention has been paid to ways in which array design can increase rare variant association power. Therefore, we developed a novel framework to select tag SNPs using the reference panel of 26 populations from Phase 3 of the 1000 Genomes Project. We evaluate tag SNP performance mean imputed r at untyped sites using leave-one-out internal validation and standard imputation methods, rather than pairwise linkage disequilibrium. Moving beyond pairwise metrics allows us to account for haplotype diversity across the genome for improve imputation accuracy and demonstrates population-specific biases from pairwise estimates. We also examine array design strategies that contrast multi-ethnic cohorts single populations, and show a boost in performance for the former can be obtained by prioritizing tag SNPs that contribute information across multiple populations simultaneously. Using our framework, we demonstrate increased imputation accuracy for rare variants (frequency < 1\%) by 0.5-3.1\% for an array of one million sites and 0.7-7.1\% for an array of 500,000 sites, depending on the population. Finally, we show how recent explosive growth in non-African populations means tag SNPs capture on average 30\% fewer other variants than in African populations. The unified framework presented here will enable investigators to make informed decisions for the design of new arrays, and help empower the next phase of rare variant association for global health.

}, keywords = {Computational Biology, Databases, Nucleic Acid, Ethnicity, Genetic Association Studies, Genetics, Population, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Models, Genetic, Polymorphism, Single Nucleotide, Reproducibility of Results, Selection, Genetic}, issn = {2160-1836}, doi = {10.1534/g3.118.200502}, author = {Wojcik, Genevieve L and Fuchsberger, Christian and Taliun, Daniel and Welch, Ryan and Martin, Alicia R and Shringarpure, Suyash and Carlson, Christopher S and Abecasis, Goncalo and Kang, Hyun Min and Boehnke, Michael and Bustamante, Carlos D and Gignoux, Christopher R and Kenny, Eimear E} } @article {32, title = {Genetic identification of a common collagen disease in puerto ricans via identity-by-descent mapping in a health system.}, journal = {Elife}, volume = {6}, year = {2017}, month = {2017 Sep 12}, abstract = {

Achieving confidence in the causality of a disease locus is a complex task that often requires supporting data from both statistical genetics and clinical genomics. Here we describe a combined approach to identify and characterize a genetic disorder that leverages distantly related patients in a health system and population-scale mapping. We utilize genomic data to uncover components of distant pedigrees, in the absence of recorded pedigree information, in the multi-ethnic Bio biobank in New York City. By linking to medical records, we discover a locus associated with both elevated genetic relatedness and extreme short stature. We link the gene, , with a little-known genetic disease, previously thought to be rare and recessive. We demonstrate that disease manifests in both heterozygotes and homozygotes, indicating a common collagen disorder impacting up to 2\% of individuals of Puerto Rican ancestry, leading to a better understanding of the continuum of complex and Mendelian disease.

}, keywords = {Adolescent, Adult, Aged, Child, Collagen Diseases, Female, Fibrillar Collagens, Genotype, Heterozygote, Hispanic or Latino, Homozygote, Humans, Male, Middle Aged, Molecular Epidemiology, Multigene Family, Musculoskeletal Diseases, New York City, Pedigree, Whole Genome Sequencing, Young Adult}, issn = {2050-084X}, doi = {10.7554/eLife.25060}, author = {Belbin, Gillian Morven and Odgis, Jacqueline and Sorokin, Elena P and Yee, Muh-Ching and Kohli, Sumita and Glicksberg, Benjamin S and Gignoux, Christopher R and Wojcik, Genevieve L and Van Vleck, Tielman and Jeff, Janina M and Linderman, Michael and Schurmann, Claudia and Ruderfer, Douglas and Cai, Xiaoqiang and Merkelson, Amanda and Justice, Anne E and Young, Kristin L and Graff, Misa and North, Kari E and Peters, Ulrike and James, Regina and Hindorff, Lucia and Kornreich, Ruth and Edelmann, Lisa and Gottesman, Omri and Stahl, Eli Ea and Cho, Judy H and Loos, Ruth Jf and Bottinger, Erwin P and Nadkarni, Girish N and Abul-Husn, Noura S and Kenny, Eimear E} } @article {14, title = {Human Demographic History Impacts Genetic Risk Prediction across Diverse Populations.}, journal = {Am J Hum Genet}, volume = {100}, year = {2017}, month = {2017 Apr 06}, pages = {635-649}, abstract = {

The vast majority of genome-wide association studies (GWASs) are performed in Europeans, and their transferability to other populations is dependent on many factors (e.g., linkage disequilibrium, allele frequencies, genetic architecture). As medical genomics studies become increasingly large and diverse, gaining insights into population history and consequently the transferability of disease risk measurement is critical. Here, we disentangle recent population history in the widely used 1000 Genomes Project reference panel, with an emphasis on populations underrepresented in medical studies. To examine the transferability of single-ancestry GWASs, we used published summary statistics to calculate polygenic risk scores for eight well-studied phenotypes. We identify directional inconsistencies in all scores; for example, height is predicted to decrease with genetic distance from Europeans, despite robust anthropological evidence that West Africans are as tall as Europeans on average. To gain deeper quantitative insights into GWAS transferability, we developed a complex trait coalescent-based simulation framework considering effects of polygenicity, causal allele frequency divergence, and heritability. As expected, correlations between true and inferred risk are typically highest in the population from which summary statistics were derived. We demonstrate that scores inferred from European GWASs are biased by genetic drift in other populations even when choosing the same causal variants and that biases in any direction are possible and unpredictable. This work cautions that summarizing findings from large-scale GWASs may have limited portability to other populations using standard approaches and highlights the need for generalized risk prediction methods and the inclusion of more diverse individuals in medical genomics.

}, keywords = {Americas, Genetic Predisposition to Disease, Genetics, Medical, Genetics, Population, Haplotypes, Human Genome Project, Humans, Multifactorial Inheritance, Racial Groups}, issn = {1537-6605}, doi = {10.1016/j.ajhg.2017.03.004}, author = {Martin, Alicia R and Gignoux, Christopher R and Walters, Raymond K and Wojcik, Genevieve L and Neale, Benjamin M and Gravel, Simon and Daly, Mark J and Bustamante, Carlos D and Kenny, Eimear E} }