Publications

Identifying segments in the genome of different individuals that are identical-by-descent (IBD) is a fundamental element of genetics. IBD data is used for numerous applications including demographic inference, heritability estimation, and mapping disease loci. Simultaneous detection of IBD over multiple haplotypes has proven to be computationally difficult. To overcome this, many state of the art methods estimate the probability of IBD between each pair of haplotypes separately. While computationally efficient, these methods fail to leverage the clique structure of IBD resulting in less powerful IBD identification, especially for small IBD segments.

Idiopathic scoliosis (IS) is a common paediatric musculoskeletal disease that displays a strong female bias. By performing a genome-wide association study (GWAS) of 3,102 individuals, we identify significant associations with 20p11.22 SNPs for females (P=6.89 × 10(-9)) but not males (P=0.71). This association with IS is also found in independent female cohorts from the United States of America and Japan (overall P=2.15 × 10(-10), OR=1.30 (rs6137473)). Unexpectedly, the 20p11.22 IS risk alleles were previously associated with protection from early-onset alopecia, another sexually dimorphic condition. The 174-kb associated locus is distal to PAX1, which encodes paired box 1, a transcription factor involved in spine development. We identify a sequence in the associated locus with enhancer activity in zebrafish somitic muscle and spinal cord, an activity that is abolished by IS-associated SNPs. We thus identify a sexually dimorphic IS susceptibility locus, and propose the first functionally defined candidate mutations in an enhancer that may regulate expression in specific spinal cells.

Highly sensitive troponin (hsTn) assays may predict cardiovascular (CV) events and left ventricular (LV) remodeling in patients with heart failure (HF). In this study, 99 subjects with LV systolic dysfunction (LVSD) were followed 10 ± 3 months with serial measurement of hsTnI by a novel method. hsTnI was detectable in all subjects and was above the 99th percentile of a normal population in 56.7 %. Supramedian baseline hsTnI concentration was associated with higher-risk clinical features and shorter time-to-first event (p = 0.008). Across serial measurements, more time spent ≤ 10.9 pg/mL was associated with a lower CV event rate after adjustment (odds ratio (OR) = 0.81; p = 0.008); rising hsTnI also predicted progressive LV remodeling. In conclusion, hsTnI detected significant myocardial necrosis in a majority of patients with chronic HF due to LVSD and when measured serially, provided independent risk information for poor CV outcomes and deleterious LV remodeling.