Devin Absher

Worldwide Human Relationships Inferred from Genome-Wide Patterns of Variation

Human genetic diversity is shaped by both demographic and biological factors and has fundamental implications for understanding the genetic basis of diseases. We studied 938 unrelated individuals from 51 populations of the Human Genome Diversity Panel at 650,000 common single-nucleotide polymorphism loci. Individual ancestry and population substructure were detectable with very high resolution. The relationship between haplotype heterozygosity and geography was consistent with the hypothesis of a serial founder effect with a single origin in sub-Saharan Africa. In addition, we observed a pattern of ancestral allele frequency distributions that reflects variation in population dynamics among geographic regions. This data set allows the most comprehensive characterization to date of human genetic variation.

Genome-wide association and meta-analysis of bipolar disorder in individuals of European ancestry

Bipolar disorder (BP) is a disabling and often life-threatening disorder that affects ≈1% of the population worldwide. To identify genetic variants that increase the risk of BP, we genotyped on the Illumina HumanHap550 Beadchip 2,076 bipolar cases and 1,676 controls of European ancestry from the National Institute of Mental Health Human Genetics Initiative Repository, and the Prechter Repository and samples collected in London, Toronto, and Dundee. We imputed SNP genotypes and tested for SNP-BP association in each sample and then performed meta-analysis across samples. The strongest association P value for this 2-study meta-analysis was 2.4 × 10−6. We next imputed SNP genotypes and tested for SNP-BP association based on the publicly available Affymetrix 500K genotype data from the Wellcome Trust Case Control Consortium for 1,868 BP cases and a reference set of 12,831 individuals. A 3-study meta-analysis of 3,683 nonoverlapping cases and 14,507 extended controls on >2.3 M genotyped and imputed SNPs resulted in 3 chromosomal regions with association P ≈ 10−7: 1p31.1 (no known genes), 3p21 (>25 known genes), and 5q15 (MCTP1). The most strongly associated nonsynonymous SNP rs1042779 (OR = 1.19, P = 1.8 × 10−7) is in the ITIH1 gene on chromosome 3, with other strongly associated nonsynonymous SNPs in GNL3, NEK4, and ITIH3. Thus, these chromosomal regions harbor genes implicated in cell cycle, neurogenesis, neuroplasticity, and neurosignaling. In addition, we replicated the reported ANK3 association results for SNP rs10994336 in the nonoverlapping GSK sample (OR = 1.37, P = 0.042). Although these results are promising, analysis of additional samples will be required to confirm that variant(s) in these regions influence BP risk.

Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study

A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single nucleotide polymorphisms (SNPs) in the risk interval in the Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics and U.S. East Asians. None of the SNPs were associated with CAD in African Americans although the power to detect an odds ratio (OR) in this group equivalent to that seen in whites was only 24-30%. ORs were higher in Hispanics and East Asians and lower in African Americans, but in all groups the 95% confidence intervals overlapped with ORs observed in whites. High-risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (P = 0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high-risk allele and presenting with CAD at age >50 years. Further investigations in other populations are needed to confirm or refute our findings.

A genome-wide association study on a southern European population identifies a new Crohn's disease susceptibility locus at RBX1-EP300

Objective Genome-wide association studies (GWAS) have identified multiple risk loci for Crohns disease (CD). However, the cumulative risk exerted by these loci is low, and the likelihood that additional, as-yet undiscovered loci contribute to the risk of CD is very high. We performed a GWAS on a southern European population to identify new CD risk loci. Design We genotyped 620 901 genome markers on 1341 CD patients and 1518 controls from Spain. The top association signals representing new candidate risk loci were subsequently analysed in an independent replication cohort of 1365 CD patients and 1396 controls. Results We identified a genome-wide significant association on chromosome 22q13.2 in the intergenic region between the RBX1 and EP300 genes (single nucleotide polymorphism rs4820425, OR 1.27, 95% CI 1.17 to 1.38, p=3.42E-8). We also found suggestive evidence for the association of the IFNGR2 (21q22.11), FOXP2 (7q31), MACROD2 (20p12.1) and AIF1 (6p21.3) loci with CD risk. Conclusions In this GWAS performed on a southern European cohort, we have identified a new risk locus for CD between RBX1 and EP300. This study demonstrates that using populations of different ancestry is a useful strategy to identify new risk loci for CD.

Fibroblast growth factor 9 is a novel modulator of negative affect

Significance Molecular mechanisms mediating negative emotion and contributing to major depression remain elusive: here, we present evidence implicating fibroblast growth factor 9 (FGF9) as a key mediator. We use whole-transcriptome studies of postmortem human tissue to demonstrate that FGF9 is elevated in depression. Reverse translation animal studies demonstrate that both endogenous and exogenous FGF9 promotes anxiety- and depression-like behavior. Conversely, localized blockade of endogenous FGF9 expression decreases anxiety behavior. To our knowledge, this paper is the first description of hippocampal FGF9 function and the first evidence implicating FGF9 in negative affect. Thus, FGF9 represents a novel target for treating affective disorders. Moreover, our findings suggest that FGF2 and FGF9 work in functional opposition; we hypothesize that the balance between FGF factors may prove critical for optimal regulation of mood. Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9’s function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.

S14-03 From trait to base pairs: Parallel evolution of pelvic reduction in three-spined sticklebacks occurs by repeated deletion of a tissue-specific pelvic enhancer at Pitx1

There are approximately 400 breeds of dog worldwide, displaying significant differences in body size, coat type, leg length, head shape, and more. We have undertaken a genome wide association study (GWAS), involving hundreds of dogs to identify the genes and mutations responsible for this range of variation. A total of 835 dogs from nearly 80 breeds were genotyped using the Affymetrix version 2.0 canine SNP chip. The dataset included 41,678 SNPs spanning all 38 autosomes and the x-chromosome after removing SNPs that had call rates of <90%, were heterozygous in >60% of individuals or could not be successfully reproduced. We then assessed the data for a large number of phenotypes. Among the most interesting traits we have focused on is disproportionate dwarfism or chondrodysplasia, a defining trait for at least nineteen breeds such as the Corgi, Dachshund and Basset Hound. Multi-breed GWAS revealed a single major locus associated with the trait. Homozygosity mapping, second generation sequencing, and cDNA analysis identified a conserved, expressed retrogene that segregates exclusively with the phenotype. In an effort to find the original source of the retrogene, we sequenced a number of dog breeds as well as a set of wolves from around the world. While the retrogenes is not present in any of the wolf populations, we do find the combination of gene and haplotype necessary to create the original retrotransposition in wolves from Europe and the Middle East. This combination was not found in any of the modern dogs breeds suggesting that the original chondrodysplastic mutation predated the formation of breeds and the ancestor of all chondrodysplastic dogs was unlike any of the breeds commonly associated with the phenotype today. Other traits have been similarly examined. To map coat variation we took advantage of both intra and inter breed differences to identify loci for three phenotypes: length, curl, and growth pattern. By comparing data from Dachshunds of differing phenotype to the larger multi-breed analysis we have been able to identify the gene and mutation that controls the facial hair growth patterns seen in breeds like schnauzers. Similarly we have found a keratin that controls the degree of curl, and a growth factor that dictates fur length. Combinations of genotypes at these three genes can account for over 90% of fur phenotypes observed among American Kennel Club (AKC) breeds, demonstrating the value of the canine system for understanding the genetic underpinnings of seemingly complex phenotypes.