Mendelian inheritance of trimodal CpG methylation sites suggests distal cis-acting genetic effects.

Environmentally influenced phenotypes, such as obesity and insulin resistance, can be transmitted over multiple generations. Epigenetic modifications, such as methylation of DNA cytosine-guanine (CpG) pairs, may be carriers of inherited information. At the population level, the methylation state of such "heritable" CpG sites is expected to follow a trimodal distribution, and their mode of inheritance should be Mendelian. Using the Illumina Infinium 450 K DNA methylation array, we determined DNA CpG-methylation in blood cells from a family cohort 123 individuals of Arab ethnicity, including 18 elementary father-mother-child trios, we asked whether Mendelian inheritance of CpG methylation is observed, and most importantly, whether it is independent of any genetic signals. Using 40× whole genome sequencing, we therefore excluded all CpG sites with possibly confounding genetic variants (SNP) within the binding regions of the Illumina probes. We identified a total of 955 CpG sites that displayed a trimodal distribution and confirmed trimodality in a study of 1805 unrelated Caucasians. Of 955 CpG sites, 99.9% observed a strict Mendelian pattern of inheritance and had no SNP within +/-110 nucleotides of the CpG site by design. However, in 97% of these cases a distal cis-acting SNP within a +/-1 Mbp window was found that explained the observed CpG distribution, excluding the hypothesis of epigenetic inheritance for these clear-cut trimodal sites. Using power analysis, we showed that in 46% of all cases, the closest CpG-associated SNP was located more than 1000 bp from the CpG site. Our findings suggest that CpG methylation is maintained over larger genomic distances. Furthermore, nearly half of the SNPs associated with these trimodal sites were also associated with the expression of nearby genes (P = 4.08 × 10(-6)), implying a regulatory effect of these trimodal CpG sites

Willingness to participate in genome testing: a survey of public attitudes from Qatar

Genomics has the potential to revolutionize medical approaches to disease prevention, diagnosis, and treatment, but it does not come without challenges. The success of a national population-based genome program, like the Qatar Genome Program (QGP), depends on the willingness of citizens to donate samples and take up genomic testing services. This study explores public attitudes of the Qatari population toward genetic testing and toward participating in the QGP. A representative sample of 837 adult Qataris was surveyed in May 2016. Approximately 71% of respondents surveyed reported that they were willing to participate in the activities of the QGP. Willingness to participate was significantly associated with basic literacy in genetics, a family history of genetic diseases, and previous experience with genetic testing through premarital screening. Respondents cited the desire to know more about their health status as the principle motivation for participating, while lack of time and information were reported as the most important barriers. With QGP plans to ramp up the scale of its national operation toward more integration into clinical care settings, it is critical to understand public attitudes and their determinants. The results demonstrate public support but also identify the need for more education and individual counseling that not only provide information on the process, challenges, and benefits of genomic testing, but that also address concerns about information security

Qatar genome: Insights on genomics from the Middle East

Despite recent biomedical breakthroughs and large genomic studies growing momentum, the Middle Eastern population, home to over 400 million people, is underrepresented in the human genome variation databases. Here we describe insights from Phase 1 of the Qatar Genome Program with whole genome sequenced 6047 individuals from Qatar. We identified more than 88 million variants of which 24 million are novel and 23 million are singletons. Consistent with the high consanguinity and founder effects in the region, we found that several rare deleterious variants were more common in the Qatari population while others seem to provide protection against diseases and have shaped the genetic architecture of adaptive phenotypes. These results highlight the value of our data as a resource to advance genetic studies in the Arab and neighboring Middle Eastern populations and will significantly boost the current efforts to improve our understanding of global patterns of human variations, human history, and genetic contributions to health and diseases in diverse populations.The Qatar Genome Program (QGP) and Qatar Biobank (QBB) are both Research and Development entities within Qatar Foundation for Education, Science and Community Development. The authors are thankful for everyone who contributed to this endeavor including the QGP and QBB team members, in addition to our partners at Hamad Medical Corporation (HMC), Sidra Medicine and other national stakeholders. The authors would like to especially thank all participants in this study for their continuous support

Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by ≥2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies

Genetic and epigenetic analysis of type 2 diabetes among Qatari families

Type 2 diabetes (T2D) is a complex multifactorial disorder driven by both genetic and environmental factors. The rapid increase of T2D in Qatar -prevalence of 16.3% in 2014 according to the International Diabetes Federation (IDF) - motivated the introduction of genetic studies among this under-presented population. Major progress to study the genetic basis of T2D came from studying common variants. However, these variants were of mild effect sizes. Studies have been shifted from applying the common variants hypothesis towards the investigation of other genetic variables including rare variants, copy number variants (CNV) and epigenetic mechanisms. This PhD project is focused on identifying genomic risk factors of T2D among the Qatari population. Eight Qatari families were analysed using the advances in genotyping and sequencing technologies. Three analyses were carried out; the aim was to identify known or novel rare variants within candidate T2D genes, identification of potential large CNVs related to T2D and detection of methylation associations with T2D. Three data sets were generated for this PhD project; these were genome-wide genotyping arrays (Illumina HumanOmni2.5M bead chip), whole genome sequencing (WGS) (Illumina hiSeq2500 platform) and genome-wide methylation arrays (Illumina 450K BeadChip capturing more than 485,577 probes). I performed three analytical experiments for the aim of this PhD project. First, linkage analysis and runs of homozygosity in combination with WGS were used to map rare variants. Second, PennCNV prediction algorithm for CNV calling was applied aiming to identify rare T2D-related CNVs. Third, association test using a linear mixed model was used for the identification of methylation associations with T2D. The findings included the identification of three rare variants detected through WGS. One variant identified within known monogenic T2D gene (GCKR) and two variants detected within known T2D genes (IGFBP2 and TGM2). These genes are functionally related to T2D and replication analysis will be required to assess their contribution to T2D among Qataris. A number of large rare CNVs detected from CNV analysis in the second experiment of the project, but potential T2D genes were not found within candidate CNVs. Also, methylation analysis replicated a significant association with T2D at cg19693031 in TXNIP (p=5.28x10¯⁶) among Qataris. The identified candidate genes were proved to be involved in the pathogenesis of T2D by causing insulin resistance and beta-cell dysfunction.Open Acces

PopPAnTe: population and pedigree association testing for quantitative data.

Family-based designs, from twin studies to isolated populations with their complex genealogical data, are a valuable resource for genetic studies of heritable molecular biomarkers. Existing software for family-based studies have mainly focused on facilitating association between response phenotypes and genetic markers, and no user-friendly tools are at present available to straightforwardly extend association studies in related samples to large datasets of generic quantitative data, as those generated by current -omics technologies. We developed PopPAnTe, a user-friendly Java program, which evaluates the association of quantitative data in related samples. Additionally, PopPAnTe implements data pre and post processing, region based testing, and empirical assessment of associations. PopPAnTe is an integrated and flexible framework for pairwise association testing in related samples with a large number of predictors and response variables. It works either with family data of any size and complexity, or, when the genealogical information is unknown, it uses genetic similarity information between individuals as those inferred from genome-wide genetic data. It can therefore be particularly useful in facilitating usage of biobank data collections from population isolates when extensive genealogical information is missing

Additional file 3: File S2. of Mendelian inheritance of trimodal CpG methylation sites suggests distal cis-acting genetic effects

Replication of 28 trimodal CpG sites that follow Mendelian inheritance in both the Qatari trios and the KORA dataset but having no Bonferroni significant underlying SNP association (based on KORA data). (PDF 200 kb