@article {91,
	title = {Assessing Digital Phenotyping to Enhance Genetic Studies of Human Diseases.},
	journal = {Am J Hum Genet},
	volume = {106},
	year = {2020},
	month = {2020 05 07},
	pages = {611-622},
	abstract = {<p>Population-scale biobanks that combine genetic data and high-dimensional phenotyping for a large number of participants provide an exciting opportunity to perform genome-wide association studies (GWAS) to identify genetic variants associated with diverse quantitative traits and diseases. A major challenge for GWAS in population biobanks is ascertaining disease cases from heterogeneous data sources such as hospital records, digital questionnaire responses, or interviews. In this study, we use genetic parameters, including genetic correlation, to evaluate whether GWAS performed using cases in the UK Biobank ascertained from hospital records, questionnaire responses, and family history of disease implicate similar disease genetics across a range of effect sizes. We find that hospital record and questionnaire GWAS largely identify similar genetic effects for many complex phenotypes and that combining together both phenotyping methods improves power to detect genetic associations. We also show that family history GWAS using cases ascertained on family history of disease agrees with combined hospital record and questionnaire GWAS and that family history GWAS has better power to detect genetic associations for some phenotypes. Overall, this work demonstrates that digital phenotyping and unstructured phenotype data can be combined with structured data such as hospital records to identify cases for GWAS in biobanks and improve the ability of such studies to identify genetic associations.</p>},
	keywords = {Asthma, Databases, Factual, Disease, Female, Genetics, Medical, Genome-Wide Association Study, Genotype, Humans, Male, Neoplasms, Phenotype, United Kingdom},
	issn = {1537-6605},
	doi = {10.1016/j.ajhg.2020.03.007},
	author = {DeBoever, Christopher and Tanigawa, Yosuke and Aguirre, Matthew and McInnes, Greg and Lavertu, Adam and Rivas, Manuel A}
}
@article {90,
	title = {Rare protein-altering variants in ANGPTL7 lower intraocular pressure and protect against glaucoma.},
	journal = {PLoS Genet},
	volume = {16},
	year = {2020},
	month = {2020 05},
	pages = {e1008682},
	abstract = {<p>Protein-altering variants that are protective against human disease provide in vivo validation of therapeutic targets. Here we use genotyping data from UK Biobank (n = 337,151 unrelated White British individuals) and FinnGen (n = 176,899) to conduct a search for protein-altering variants conferring lower intraocular pressure (IOP) and protection against glaucoma. Through rare protein-altering variant association analysis, we find a missense variant in ANGPTL7 in UK Biobank (rs28991009, p.Gln175His, MAF = 0.8\%, genotyped in 82,253 individuals with measured IOP and an independent set of 4,238 glaucoma patients and 250,660 controls) that significantly lowers IOP (β = -0.53 and -0.67 mmHg for heterozygotes, -3.40 and -2.37 mmHg for homozygotes, P = 5.96 x 10-9 and 1.07 x 10-13 for corneal compensated and Goldman-correlated IOP, respectively) and is associated with 34\% reduced risk of glaucoma (P = 0.0062). In FinnGen, we identify an ANGPTL7 missense variant at a greater than 50-fold increased frequency in Finland compared with other populations (rs147660927, p.Arg220Cys, MAF Finland = 4.3\%), which was genotyped in 6,537 glaucoma patients and 170,362 controls and is associated with a 29\% lower glaucoma risk (P = 1.9 x 10-12 for all glaucoma types and also protection against its subtypes including exfoliation, primary open-angle, and primary angle-closure). We further find three rarer variants in UK Biobank, including a protein-truncating variant, which confer a strong composite lowering of IOP (P = 0.0012 and 0.24 for Goldman-correlated and corneal compensated IOP, respectively), suggesting the protective mechanism likely resides in the loss of interaction or function. Our results support inhibition or down-regulation of ANGPTL7 as a therapeutic strategy for glaucoma.</p>},
	keywords = {Adult, Aged, Aged, 80 and over, Angiopoietin-like Proteins, Biological Specimen Banks, Case-Control Studies, Cohort Studies, Female, Finland, Gene Frequency, Genetic Predisposition to Disease, Genetics, Population, Genome-Wide Association Study, Glaucoma, Humans, Intraocular Pressure, Loss of Function Mutation, Male, Middle Aged, Mutation, Missense, Polymorphism, Single Nucleotide, United Kingdom},
	issn = {1553-7404},
	doi = {10.1371/journal.pgen.1008682},
	author = {Tanigawa, Yosuke and Wainberg, Michael and Karjalainen, Juha and Kiiskinen, Tuomo and Venkataraman, Guhan and Lemmel{\"a}, Susanna and Turunen, Joni A and Graham, Robert R and Havulinna, Aki S and Perola, Markus and Palotie, Aarno and Daly, Mark J and Rivas, Manuel A}
}
