Genometric analysis of quantitative traits

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SUMMARY Administrative Note The number of ongoing projects, and the number of intramural and extramural collaborators has been substantially reduced because of Dr. Wilsons upcoming retirement in September 2020. The focus of the Genometrics Section over the past year has been to complete ongoing collaborations. Effort has been focused on winding down the current research portfolio. This is the final annual report for the Genometric Analysis of Quantitative Traits project. The last post-doctoral IRTA fellow, Dr. Jeremy Sabourin has taken a position with Biostat Solutions in Frederick, MD. The Staff Scientists in the Genometrics Section have been placed in other equivalent positions at NIH. Dr. Heejong Sung has moved to the National Institute of Mental Health under the direction of Dr. Francis McMahon. Dr. Cristina Justice and Alexa Sorant remain in NHGRI; Dr. Justice under the direction of Dr. Philip Shaw, and Ms. Sorant under the direction of Dr. Joan Bailey-Wilson. Dr. Wilson will continue, part-time, as a special volunteer, or if approved, as an Emeritus Scientist. Software Development Final versions of three projects are now available. In the first, the tiled regression methodology was updated in the Tiled Regression Analysis Package (TRAP). Version 2.0 of TRAP includes additional penalized regression models and is available on the NHGRI website: http://research.nhgri.nih.gov/software/TRAP. In the second project, a faster version of TRAP for quantitative traits (TR-Quant) is now available at https://research.nhgri.nih.gov/software/TRQUANT. And, in the third, software for ComPaSS-GWAS Sabourin et al. 2019 is now available at https://research.nhgri.nih.gov/software/compass-gwas. This version of ComPaSS-GWAS is limited to analysis with PLINK. Collaborations Craniosynostosis As part of an ongoing collaboration with Dr. Simeon Boyd (UC Davis) and Dr. Paul Romiti (U of Iowa) Justice et al. 2012 reported a genome-wide association study (GWAS) for sagittal non-syndromic craniosynostosis (sNCS). This same approach was applied to 215 non-Hispanic parent-offspring trios with metopic non-syndromic craniosynostosis (mNCS). Six variants were identified that were genome-wide significant and one of the variants was replicated in an independent non-Hispanic white sample of 194 unrelated mNCS cases and 333 unaffected controls. A meta-analysis of SNPs common to both the mNCS and sNCS studies identified a single SNP at the genome-wide association suggestive level of 1x10-5. Results from a luciferase studies suggested that a fragment which encompasses this SNP acts as a repressor element. This work was recently published in Human Genetics. Measurement of caf-au-lait macules in NF1 patients. As part of an ongoing collaboration with Dr. Douglas Stewart (NCI), a follow-up to our genome-wide association study of modifiers for a genome-wide association analysis was performed focusing on the number of caf-au-lait macules (CALM) as a clinical phenotype modifying NF1. A borderline genome-wide significant association was identified in the discovery cohort. This association was not replicated in the second cohort and a meta-analysis did not show significantly associated variants with this variant. However, a significant corroboration score (0.72) was obtained for this SNP in the discovery cohort using Complementary Pairs Stability Selection (ComPaSS-GWAS) analysis Sabourin, 2019 suggesting that the lack of replication may be due to heterogeneity of the cohorts rather than type I error. This work is in press in Molecular Genetic and Genomic Medicine 2020. Other ongoing collaborations 1) The ClinSeq project (Les Biesecker, NIH/NHGRI) 2) Statistical properties of fixed and mixed effects models. Dr. Ruzong Fan, Georgetown University. 3) Genetics of traits related to vitamin D metabolism. Dr. Larry Brody, NHGRI, Dr. Barry Shane, Dr. Faith Pangilinan (Trinity College, Ireland). 4) Cardiovascular and metabolic traits in non-Europeans in the UK BioBank database (Dr. Teri Manolio, NHGRI).