Leveraging Multi-ethnic Evidence for Mapping Complex Traits in Minority Populations: An Empirical Bayes Approach

Elucidating the genetic basis of complex traits and diseases in non-European populations is particularly challenging because US minority populations have been under-represented in genetic association studies. We developed an empirical Bayes approach named XPEB (cross-population empirical Bayes), designed to improve the power for mapping complex-trait-associated loci in a minority population by exploiting information from genome-wide association studies (GWASs) from another ethnic population. Taking as input summary statistics from two GWASs—a target GWAS from an ethnic minority population of primary interest and an auxiliary base GWAS (such as a larger GWAS in Europeans)—our XPEB approach reprioritizes SNPs in the target population to compute local false-discovery rates. We demonstrated, through simulations, that whenever the base GWAS harbors relevant information, XPEB gains efficiency. Moreover, XPEB has the ability to discard irrelevant auxiliary information, providing a safeguard against inflated false-discovery rates due to genetic heterogeneity between populations. Applied to a blood-lipids study in African Americans, XPEB more than quadrupled the discoveries from the conventional approach, which used a target GWAS alone, bringing the number of significant loci from 14 to 65. Thus, XPEB offers a flexible framework for mapping complex traits in minority populations

Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects and tissue-specific enrichment of eQTLs

We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci

Integrative analysis of RNA, translation, and protein levels reveals distinct regulatory variation across humans

International audienceElucidating the consequences of genetic differences between humans is essential for understanding phenotypic diversity and personalized medicine. Although variation in RNA levels, transcription factor binding, and chromatin have been explored, little is known about global variation in translation and its genetic determinants. We used ribosome profiling, RNA sequencing, and mass spectrometry to perform an integrated analysis in lymphoblastoid cell lines from a diverse group of individuals. We find significant differences in RNA, translation, and protein levels suggesting diverse mechanisms of personalized gene expression control. Combined analysis of RNA expression and ribosome occupancy improves the identification of individual protein level differences. Finally, we identify genetic differences that specifically modulate ribosome occupancy-many of these differences lie close to start codons and upstream ORFs. Our results reveal a new level of gene expression variation among humans and indicate that genetic variants can cause changes in protein levels through effects on translation

Model for Acquisition of Dorsoventral Patterning in the Trunk and the Role of <i>Tbx15</i>

<div><p>(A) A tricolor pigmentation pattern is generated by the combination of distinct mechanisms that affect distribution of <i>Agouti</i> mRNA and histochemical staining for melanocytes; effects of the latter mechanism by itself are evident in <i>a^e</i>/<i>a^e</i> mice (see <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020003#pbio-0020003-g001" target="_blank">Figure 1</a>). In <i>a^t/a^t</i> mice, reduced hair melanocyte activity and high levels of <i>Agouti</i> mRNA in the ventrum lead to a cream color; as melanocyte activity gradually increases towards the dorsum, a lateral stripe is apparent on the flank. The distributions of <i>Agouti</i> mRNA and histochemical staining for melanocytes are both affected by <i>Tbx15</i> and are externally evident by a widening of the lateral stripe and an increased proportion of total skin occupied by the cream-colored area.</p> <p>(B) The lateral yellow stripe in <i>a^t/a^t</i> mice lies at the same level as the limb dorsoventral boundary. As described in the text, we propose that distinct dorsoventral compartments in ectoderm of the trunk provide an instructional cue to the mesoderm, leading to expression of <i>Tbx15</i> in dorsal trunk mesenchyme and acquisition of dorsal dermis character. In the absence of <i>Tbx15</i>, dorsal mesenchyme assumes ventral characteristics instead.</p></div

Embryonic Expression of <i>Tbx15</i> Compared to <i>Agouti</i> in <i>a^t</i>/<i>a^t</i> Mice

<p>(A and C) <i>Tbx15</i>. (B and D) <i>Agouti</i>. At E12.5, expression of <i>Tbx15</i> in dorsal skin is approximately complementary to that of <i>Agouti</i> in ventral skin. At E14.5, the levels of expression for both genes are lower, but <i>Tbx15</i> expression has expanded ventrally and overlaps extensively with that of <i>Agouti</i>. In all four panels, arrows mark the approximate ventral limit of <i>Tbx15</i> and the approximate dorsal limit of <i>Agouti</i> (scale bars = 500 μm).</p

Effect of <i>de^H</i> on <i>Agouti</i> Expression

<div><p>Comparable sections from <i>a^t/a^t</i>; <i>de^H</i>/<i>de^H</i> and <i>a^t/a^t</i>; +/+ littermates.</p> <p>(A) At E14.5, <i>de^H</i>/<i>de^H</i> embryos have a smaller body cavity and loose skin within which <i>Agouti</i> expression appears to be shifted dorsally, as marked by arrows (scale bars = 500 μm).</p> <p>(B) At P4.5, <i>Agouti</i> expression in both dorsal and ventral skin is similar in <i>de^H</i>/<i>de^H</i> compared to nonmutant, but in the midflank region, there is increased <i>Agouti</i> expression in <i>de^H</i>/<i>de^H</i>, especially in the upper dermis (scale bars = 200 μm). Sections shown are representative of two mutant and two nonmutant samples examined at each time.</p></div

Developmental Expression of <i>Tbx15</i>

<div><p>(A) At E12.5, transverse sections at different levels show expression in head mesenchyme (a and b); myotome, occipital, and periocular mesenchyme (b); palatal shelf, cervical sclerotome, and nasal cartilage (c); maxillary and mandibular processes (d); limbs (e); and myotome and lateral mesenchyme (e and f) (scale bars = 500 μm).</p> <p>(B) Transverse sections through the flank at different times show expression in lateral mesenchyme (E11.5), expanding dorsally at E12.5, and both ventrally and dorsally at E13.5, detectable in loose mesenchyme underlying the dermis and the abdominal and subcutaneous muscles (scale bar = 500 μm). At P3.5, <i>Tbx15</i> is expressed in the entire dermis and is most strongly expressed in dermal sheaths (scale bar = 200 μm).</p></div

The <i>de^H</i> Pigmentation Phenotype

<div><p>(A) 10-wk-old <i>de^H/de^H</i> and nonmutant animals on a <i>a^t</i> background. A thin stripe of yellow hair normally separates the dorsal black hairs from the ventral cream hairs. In <i>de^H</i>, the yellow stripe is extended dorsally, and the boundary between the yellow and the black hairs is fuzzier.</p> <p>(B) Skin slices taken from 1.5-mo-old <i>de^H/de^H</i> and nonmutant littermates (scale bar = 0.5 cm).</p> <p>(C) Proportion of total skin area as determined by observation of pelts taken from the interlimb region. The proportion occupied by the yellow lateral compartment (± SEM) differs between mutant and nonmutant littermate flanks (<i>p</i> < 0.0005, paired <i>t</i>-test, <i>n</i> = 6 pairs). There is also (data not shown) a small increase in the proportion of total skin area occupied by the ventral cream-colored compartment, 47.9 % in mutant compared to 37.8% in nonmutant (<i>p</i> < 0.005, paired <i>t</i>-test, <i>n</i> = 6 pairs).</p> <p>(D) On an <i>a^e/a^e</i> background, the extent of dorsal skin pigmentation is reduced in <i>de^H/de^H</i> neonates (P3.5).</p> <p>(E) Hair length in a representative pair of 1.5-mo-old <i>de^H/de^H</i> and nonmutant littermates, averaged over three skin slices at different rostrocaudal levels, and plotted as a function of the absolute distance from middorsum or the percentage of total slice length.</p></div

Dorsoventral Skin Characteristics

<div><p>(A) Skin slices from animals of different age and genotype demonstrate similar patterns of hair-length variation along the dorsoventral axis (scale bar = 1 cm).</p> <p>(B) Enlarged area from (A), demonstrating the transition in hair length and color in <i>a^t</i>/<i>a^t</i> mice (scale bar = 0.375 cm).</p> <p>(C) Proportional hair length for (A) plotted as a function of relative position along the dorsoventral axis.</p> <p>(D) Hair length plotted as a function of absolute position along the dorsoventral axis for 8-wk-old BA strain mice.</p> <p>(E) Proportion of zigzag hairs (± SEM) differs slightly between dorsum and ventrum of inbred mice (<i>p</i> < 0.0001, χ² test, <i>n</i> = 1,958, 1,477, 1,579, 1,502).</p> <p>(F) Differences in dorsal and ventral skin development at P4.5 (scale bar = 1 mm, upper; 200 μm, lower).</p> <p>(G) Differences in hair melanin content and DOPA staining for dorsum (d), flank (f), and ventrum (v) in <i>a^e</i>/<i>a^e</i> and <i>a^t</i>/<i>a^t</i> mice. The upper panel also demonstrates a cream-colored appearance of the <i>a^t</i>/<i>a^t</i> ventrum. The middle panel shows representative awls (scale bar = 100 μm). The lower panel shows DOPA-stained dermis (scale bar = 200 μm).</p></div