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Exploring the dark genome: implications for precision medicine.

ABSTRACT: The increase in the number of both patients and healthcare practitioners who grew up using the Internet and computers (so-called "digital natives") is likely to impact the practice of precision medicine, and requires novel platforms for data integration and mining, as well as contextualized information retrieval. The "Illuminating the Druggable Genome Knowledge Management Center" (IDG KMC) quantifies data availability from a wide range of chemical, biological, and clinical resources, and has developed platforms that can be used to navigate understudied proteins (the "dark genome"), and their potential contribution to specific pathologies. Using the "Target Importance and Novelty Explorer" (TIN-X) highlights the role of LRRC10 (a dark gene) in dilated cardiomyopathy. Combining mouse and human phenotype data leads to increased strength of evidence, which is discussed for four additional dark genes: SLX4IP and its role in glucose metabolism, the role of HSF2BP in coronary artery disease, the involvement of ELFN1 in attention-deficit hyperactivity disorder and the role of VPS13D in mouse neural tube development and its confirmed role in childhood onset movement disorders. The workflow and tools described here are aimed at guiding further experimental research, particularly within the context of precision medicine.

SUBMITTER: Oprea TI

PROVIDER: S-EPMC6836689 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Exploring the dark genome: implications for precision medicine.

Oprea Tudor I TI

Mammalian genome : official journal of the International Mammalian Genome Society 20190704 7-8

The increase in the number of both patients and healthcare practitioners who grew up using the Internet and computers (so-called "digital natives") is likely to impact the practice of precision medicine, and requires novel platforms for data integration and mining, as well as contextualized information retrieval. The "Illuminating the Druggable Genome Knowledge Management Center" (IDG KMC) quantifies data availability from a wide range of chemical, biological, and clinical resources, and has dev ...[more]

PMID: 31270560

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Project description:BackgroundWe have previously shown that the effect of a high-density lipoprotein (HDL) genetic risk score depends on whether the phenotype (HDL cholesterol) is high or low relative to its distribution (quantile-dependent expressivity).ObjectiveEvidence for quantile-dependent expressivity was sought using a more inclusive genetic measure (quantile-specific heritability, h2) in a larger population (Framingham cohort).MethodsQuantile regression was used to test whether the offspring-parent (βOP) and full-sib (βFS) regression slopes increased with the percentiles of the offspring's HDL distribution in 10,650 parent-offspring pairs and 2130 sibships. Quantile-specific heritability was estimated by 2βOP/(1 + rspouse) and [(8βFSrspouse + 1)0.5-1]/(2rspouse), where rspouse is the spouse correlation.ResultsHDL cholesterol heritability estimated from βOP increased significantly (P = 4.2 × 10-5) from the 10th (h2 ± SE: 0.44 ± 0.03), 25th (0.45 ± 0.03), 50th (0.47 ± 0.03), and 75th (0.56 ± 0.04) to the 90th percentiles (0.65 ± 0.06) of the offspring's age- and sex-adjusted HDL cholesterol distribution. Heritability estimated from βFS also increased significantly with the percentiles of the offspring's HDL cholesterol (P = .002), apo A1 (P = .006), HDL2 cholesterol (P = .003), and HDL3 cholesterol distribution (P = .02). Consistent with quantile-dependent expressivity, published pharmacologic and nutritional interventions that raised (eg, statin, fibrates, estrogen replacement therapy, efavirenz, and dietary fat) or lowered HDL cholesterol concentrations (tamoxifen, dietary carbohydrate) correspondingly increased and decreased genetic effects.ConclusionHDL cholesterol heritability increased with increasing percentile of the offspring's HDL distribution. Whereas precision medicine is based on the premise that genetic markers identify patients most likely to benefit from drugs and diet, quantile-dependent expressivity postulates that the strong signals from these genetic markers simply trace the heritability increase with increasing plasma HDL concentrations. Thus, quantile-dependent expressivity provides an alternative interpretation to these genotype-specific effects.

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Exploring the dark genome: implications for precision medicine.

Publications

Exploring the dark genome: implications for precision medicine.

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