Methods Development Ad-hoc replication with Complementary Pairs Stability Selection (ComPaSS) Results from association studies are traditionally corroborated by replicating the findings in an independent dataset. Although replication studies may be comparable for the main trait or phenotype of interest, it is unlikely that secondary phenotypes will be comparable across studies, making replication problematic. Alternatively, there may simply not be a replication sample available because of the nature or frequency of the phenotype. In these situations, an approach based on complementary-pairs stability selection, ComPaSS-GWAS, is proposed as an ad-hoc alternative to replication. In this new method, the sample is randomly split into two conditionally independent halves multiple times (resamples) and a GWAS is performed on each half in each resample. Similar in spirit to testing for association with independent discovery and replication samples, a marker is corroborated if its p-value is significant in both halves of the resample. Simulation experiments were performed for both non-genetic (null model) and genetic models. The type I error rate and power of ComPaSS-GWAS were determined and compared to the statistical properties of a traditional GWAS. Simulation results show that the type I error rate decreased as the number of resamples increased with only a small reduction in power and that these results were comparable to those from a traditional GWAS. Blood levels of vitamin pyridoxal 5-phosphate (PLP) from the TSS were used to validate this approach. The results from the validation study were compared to, and were consistent with, those obtained from previously published independent replication data and functional studies Sabourin et al. in press. Software Development Software development and implementation has focused on two projects during the past year. In the first, the tiled regression methodology was updated in the Tiled Regression Analysis Package (TRAP); version 2.0 of the software includes additional penalized regression models and was released in May, 2017. In addition, a faster version of Tiled Regression was implemented as TR-Quant. The TRAP package is available on the NHGRI website: http://research.nhgri.nih.gov/software/TRAP. TR-Quant will be available this fall. In the second, software for ComPaSS-GWAS Sabourin et al. in press is being prepared for release and should be available when the paper is published. It is currently limited to analysis with PLINK. Collaborations Genetics of Brain Growth Genome-wide association studies (GWASs) are unraveling the genetics of adult brain neuroanatomy as measured by cross-sectional anatomic magnetic resonance imaging (aMRI). However, the genetic mechanisms that shape childhood brain development are, as yet, largely unexplored. In this study common genetic variants associated with childhood brain development as defined by longitudinal aMRI were identified. Genome-wide single nucleotide polymorphism (SNP) data were determined in two cohorts: one enriched for attention-deficit/hyperactivity disorder (ADHD) (LONG cohort: 458 participants; 119 with ADHD) and the other from a population-based cohort (Generation R: 257 participants). The growth of the brain's major regions (cerebral cortex, white matter, basal ganglia, and cerebellum) and one region of interest (the right lateral prefrontal cortex) were defined on all individuals from two aMRIs, and a GWAS and a pathway analysis were performed. In addition, association between polygenic risk for ADHD and brain growth was determined for the LONG cohort. For white matter growth, GWAS meta-analysis identified a genome-wide significant intergenic SNP (rs12386571, P = 9.09 109), near AKR1B10. This gene is part of the aldoketo-reductase superfamily and shows neural expression. No enrichment of neural pathways was detected and polygenic risk for ADHD was not associated with the brain growth phenotypes in the LONG cohort that was enriched for the diagnosis of ADHD. The study illustrates the use of a novel brain growth phenotype defined in vivo for further study. Craniosynostosis Justice et al. 2012 reported a genome-wide association study (GWAS) for non-syndromic sagittal craniosynostosis and these associations were replicated in an independent Caucasian population of 186 unrelated probands with non-syndromic sagittal craniosynostosis and 564 unaffected controls. Zebra fish were used to test the expression of the previously identified conserved non-coding regulatory elements to determine if the expression of identified sequence variants differed from that of the wild type expression. To accomplish this, a putative regulatory element was created with site-directed mutagenesis and inserted into the Zebra fish Enhancer Detection (ZED) vector construct. The embryos were screened with fluorescent microscopy for red and green florescent protein (RFP and GFP, respectively) positive embryos. Embryos demonstrating RFP/GRP expression were grown to adulthood and bred with wild type fish. Several germline transmitting founders were identified for each ZED vector construct and their progeny were screened for patterns of RFP/GFP expression, again using fluorescent microscopy. GFP expression in the fish with the risk allele (C) appears to occur in the midbrain and hindbrain, while in the fish with the wild type (T) allele, GFP expression was observed in the midbrain-hindbrain boundary. This work was featured on the cover of Genetic Epidemiology Justice et al. 2017. Other ongoing collaborations 1) The ClinSeq project (Les Biesecker, NIH/NHGRI) 2) Statistical properties of fixed and mixed effects models. Dr. Ruzong Fan, NIH/NICHD and Georgetown University. 3) Measurement of caf-au-lait macules in NF1 patients. Dr. Douglas Stewart, NCI. 4) Genetics of traits related to vitamin D metabolism. Dr. Larry Brody, NHGRI, Dr. Barry Shane ( ), Dr. Faith Pangilinan (Trinity College, Ireland).
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