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Langefeld, C. D.

Publications and source records attributed to Langefeld, C. D..

2 recordsLinked to original sources
bioRxiv2019

Intrinsic DNA topology as a prioritization metric in genomic fine-mapping studies

In genomic fine-mapping studies, some approaches leverage annotation data to prioritize likely functional polymorphisms. However, existing annotation sources often present challenges as many: lack data for novel variants, offer no context for noncoding regions, and/or are confounded with linkage disequilibrium. We propose a novel annotation source - sequence-dependent DNA topology - as a prioritization metric for fine-mapping. DNA topology and function are well-intertwined, and as an intrinsic DNA property, it is readily applicable to any genomic region. Here, we constructed and applied, Minor Groove Width (MGW), as a prioritization metric. Using an established MGW-prediction method, we generated an MGW census for 199,038,197 SNPs across the human genome. Summarizing a SNPs change in MGW ({Delta}MGW) as a Euclidean distance, {Delta}MGW exhibited a strongly right-skewed distribution, highlighting the infrequency of SNPs that generate dissimilar shape profiles. We hypothesized that phenotypically-associated SNPs can be prioritized by {Delta}MGW. We applied Bayesian and frequentist MGW-prioritization approaches to three non-coding regions associated with System Lupus Erythematosus in multiple ancestries. In two regions, including {Delta}MGW resolved the association to a single, trans-ancestral, SNP, corroborated by external functional data. Together, this study presents the first usage of sequence-dependent DNA topology as a prioritization metric in genomic association studies. Graphical AbstractWe hypothesize that SNPs imposing dissimilar minor groove width profiles ({Delta}MGW) are more likely to alter function. {Delta}MGW was interrogated genome-wide and then used as a weighting metric for fine-mapping associations. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=153 SRC="FIGDIR/small/837245v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@d350adorg.highwire.dtl.DTLVardef@155a2cborg.highwire.dtl.DTLVardef@132e30aorg.highwire.dtl.DTLVardef@1d7b065_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗
bioRxiv2019

Complement component 4 genes contribute sex-specific vulnerability in diverse illnesses

Many common illnesses differentially affect men and women for unknown reasons. The autoimmune diseases lupus and Sjogrens syndrome affect nine times more women than men1,2, whereas schizophrenia affects men more frequently and severely3-5. All three illnesses have their strongest common-genetic associations in the Major Histocompatibility Complex (MHC) locus, an association that in lupus and Sjogrens syndrome has long been thought to arise from HLA alleles6-13. Here we show that the complement component 4 (C4) genes in the MHC locus, recently found to increase risk for schizophrenia14, generate 7-fold variation in risk for lupus (95% CI: 5.88-8.61; p < 10-117 in total) and 16-fold variation in risk for Sjogrens syndrome (95% CI: 8.59-30.89; p < 10-23 in total), with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia, greatly reduced risk for lupus and Sjogrens syndrome. In all three illnesses, C4 alleles acted more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for lupus and 31-fold variation in risk for Sjogrens syndrome in men (vs. 6-fold and 15-fold among women respectively) and affected schizophrenia risk about twice as strongly in men as in women. At a protein level, both C4 and its effector (C3) were present at greater levels in men than women in cerebrospinal fluid (p < 10-5 for both C4 and C3) and plasma among adults ages 20-5015-17, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help explain the larger effects of C4 alleles in men, womens greater risk of SLE and Sjogrens, and mens greater vulnerability in schizophrenia. These results nominate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

genetics↗