Publications by authors named "Diana L Cousminer"

54 Publications

3D promoter architecture re-organization during iPSC-derived neuronal cell differentiation implicates target genes for neurodevelopmental disorders.

Prog Neurobiol 2021 06 2;201:102000. Epub 2021 Feb 2.

Division of Human Genetics, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA, United States; Division of Diabetes and Endocrinology, The Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA, United States; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA, United States; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, 3615 Civic Center Boulevard, Philadelphia, PA, United States. Electronic address:

Neurodevelopmental disorders are thought to arise from interrupted development of the brain at an early age. Genome-wide association studies (GWAS) have identified hundreds of loci associated with susceptibility to neurodevelopmental disorders; however, which noncoding variants regulate which genes at these loci is often unclear. To implicate neuronal GWAS effector genes, we performed an integrated analysis of transcriptomics, epigenomics and chromatin conformation changes during the development from Induced pluripotent stem cell-derived neuronal progenitor cells (NPCs) into neurons using a combination of high-resolution promoter-focused Capture-C, ATAC-seq and RNA-seq. We observed that gene expression changes during the NPC-to-neuron transition were highly dependent on both promoter accessibility changes and long-range interactions which connect distal cis-regulatory elements (enhancer or silencers) to developmental-stage-specific genes. These genome-scale promoter-cis-regulatory-element atlases implicated 454 neurodevelopmental disorder-associated, putative causal variants mapping to 600 distal targets. These putative effector genes were significantly enriched for pathways involved in the regulation of neuronal development and chromatin organization, with 27 % expressed in a stage-specific manner. The intersection of open chromatin and chromatin conformation revealed development-stage-specific gene regulatory architectures during neuronal differentiation, providing a rich resource to aid characterization of the genetic and developmental basis of neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pneurobio.2021.102000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8096691PMC
June 2021

Biological constraints on GWAS SNPs at suggestive significance thresholds reveal additional BMI loci.

Elife 2021 Jan 18;10. Epub 2021 Jan 18.

Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, United States.

To uncover novel significant association signals (p<5×10), genome-wide association studies (GWAS) requires increasingly larger sample sizes to overcome statistical correction for multiple testing. As an alternative, we aimed to identify associations among suggestive signals (5 × 10≤p<5×10) in increasingly powered GWAS efforts using chromatin accessibility and direct contact with gene promoters as biological constraints. We conducted retrospective analyses of three GIANT BMI GWAS efforts using ATAC-seq and promoter-focused Capture C data from human adipocytes and embryonic stem cell (ESC)-derived hypothalamic-like neurons. This approach, with its extremely low false-positive rate, identified 15 loci at p<5×10 in the 2010 GWAS, of which 13 achieved genome-wide significance by 2018, including at , , and . Eighty percent of constrained 2015 loci achieved genome-wide significance in 2018. We observed similar results in waist-to-hip ratio analyses. In conclusion, biological constraints on sub-significant GWAS signals can reveal potentially true-positive loci for further investigation in existing data sets without increasing sample size.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.62206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815306PMC
January 2021

Genome-wide association study implicates novel loci and reveals candidate effector genes for longitudinal pediatric bone accrual.

Genome Biol 2021 01 4;22(1). Epub 2021 Jan 4.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: Bone accrual impacts lifelong skeletal health, but genetic discovery has been primarily limited to cross-sectional study designs and hampered by uncertainty about target effector genes. Here, we capture this dynamic phenotype by modeling longitudinal bone accrual across 11,000 bone scans in a cohort of healthy children and adolescents, followed by genome-wide association studies (GWAS) and variant-to-gene mapping with functional follow-up.

Results: We identify 40 loci, 35 not previously reported, with various degrees of supportive evidence, half residing in topological associated domains harboring known bone genes. Of several loci potentially associated with later-life fracture risk, a candidate SNP lookup provides the most compelling evidence for rs11195210 (SMC3). Variant-to-gene mapping combining ATAC-seq to assay open chromatin with high-resolution promoter-focused Capture C identifies contacts between GWAS loci and nearby gene promoters. siRNA knockdown of gene expression supports the putative effector gene at three specific loci in two osteoblast cell models. Finally, using CRISPR-Cas9 genome editing, we confirm that the immediate genomic region harboring the putative causal SNP influences PRPF38A expression, a location which is predicted to coincide with a set of binding sites for relevant transcription factors.

Conclusions: Using a new longitudinal approach, we expand the number of genetic loci putatively associated with pediatric bone gain. Functional follow-up in appropriate cell models finds novel candidate genes impacting bone accrual. Our data also raise the possibility that the cell fate decision between osteogenic and adipogenic lineages is important in normal bone accrual.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13059-020-02207-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780623PMC
January 2021

Insights into the Genetic Underpinnings of Endocrine Traits from Large-Scale Genome-Wide Association Studies.

Endocrinol Metab Clin North Am 2020 12;49(4):725-739

Center for Spatial and Functional Genomics, Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Clinical Research Building 500, 415 Curie Boulevard, Philadelphia, PA 19104, USA. Electronic address:

Great strides have been made in genetic association studies of endocrine traits and diseases, with hundreds or thousands of variants associated with height, body mass index, bone density, pubertal timing, and diabetes in recent years. The common variants associated with these traits explain up to half of the trait variation owing to genetic factors, and when aggregated into polygenic risk scores, can also impact clinically relevant phenotypes at the tail ends of the trait distributions. However, pediatric studies tend to lag behind, and it is often unclear how adult-associated variants behave across life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ecl.2020.07.007DOI Listing
December 2020

Variant-to-Gene-Mapping Analyses Reveal a Role for the Hypothalamus in Genetic Susceptibility to Inflammatory Bowel Disease.

Cell Mol Gastroenterol Hepatol 2021 16;11(3):667-682. Epub 2020 Oct 16.

Center for Spatial and Functional Genomics, Philadelphia, Pennsylvania; Division of Human Genetics, Philadelphia, Pennsylvania; Division of Diabetes and Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:

Background & Aims: Inflammatory bowel disease (IBD) is a polygenic disorder characterized principally by dysregulated inflammation impacting the gastrointestinal tract. However, there also is increasing evidence for a clinical association with stress and depression. Given the role of the hypothalamus in stress responses and in the pathogenesis of depression, useful insights could be gleaned from understanding its genetic role in IBD.

Methods: We conducted genetic correlation analyses on publicly available genome-wide association study summary statistics for depression and IBD traits to identify genetic commonalities. We used partitioned linkage disequilibrium score regression, leveraging our ATAC sequencing and promoter-focused Capture C data, to measure enrichment of IBD single-nucleotide polymorphisms within promoter-interacting open chromatin regions of human embryonic stem cell-derived hypothalamic-like neurons (HNs). Using the same data sets, we performed variant-to-gene mapping to implicate putative IBD effector genes in HNs. To contrast these results, we similarly analyzed 3-dimensional genomic data generated in epithelium-derived colonoids from rectal biopsy specimens from donors without pathologic disease noted at the time of colonoscopy. Finally, we conducted enrichment pathway analyses on the implicated genes to identify putative IBD dysfunctional pathways.

Results: We found significant genetic correlations (rg) of 0.122 with an adjusted P (P) = 1.4 × 10 for IBD: rg = 0.122; P = 2.5 × 10 for ulcerative colitis and genetic correlation (rg) = 0.094; P = 2.5 × 10 for Crohn's disease, and significant approximately 4-fold (P = .005) and approximately 7-fold (P = .03) enrichment of IBD single-nucleotide polymorphisms in HNs and colonoids, respectively. We implicated 25 associated genes in HNs, among which CREM, CNTF, and RHOA encode key regulators of stress. Seven genes also additionally were implicated in the colonoids. We observed an overall enrichment for immune and hormonal signaling pathways, and a colonoid-specific enrichment for microbiota-relevant terms.

Conclusions: Our results suggest that the hypothalamus warrants further study in the context of IBD pathogenesis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jcmgh.2020.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843407PMC
October 2020

Novel loci for childhood body mass index and shared heritability with adult cardiometabolic traits.

PLoS Genet 2020 10 12;16(10):e1008718. Epub 2020 Oct 12.

Department of Public Health, Amsterdam Public Health Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

The genetic background of childhood body mass index (BMI), and the extent to which the well-known associations of childhood BMI with adult diseases are explained by shared genetic factors, are largely unknown. We performed a genome-wide association study meta-analysis of BMI in 61,111 children aged between 2 and 10 years. Twenty-five independent loci reached genome-wide significance in the combined discovery and replication analyses. Two of these, located near NEDD4L and SLC45A3, have not previously been reported in relation to either childhood or adult BMI. Positive genetic correlations of childhood BMI with birth weight and adult BMI, waist-to-hip ratio, diastolic blood pressure and type 2 diabetes were detected (Rg ranging from 0.11 to 0.76, P-values <0.002). A negative genetic correlation of childhood BMI with age at menarche was observed. Our results suggest that the biological processes underlying childhood BMI largely, but not completely, overlap with those underlying adult BMI. The well-known observational associations of BMI in childhood with cardio-metabolic diseases in adulthood may reflect partial genetic overlap, but in light of previous evidence, it is also likely that they are explained through phenotypic continuity of BMI from childhood into adulthood.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.pgen.1008718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581004PMC
October 2020

Regulation of cellular sterol homeostasis by the oxygen responsive noncoding RNA lincNORS.

Nat Commun 2020 09 21;11(1):4755. Epub 2020 Sep 21.

Rogel Cancer Center, University of Michigan, Ann Arbor, MI, 48109, USA.

We hereby provide the initial portrait of lincNORS, a spliced lincRNA generated by the MIR193BHG locus, entirely distinct from the previously described miR-193b-365a tandem. While inducible by low O in a variety of cells and associated with hypoxia in vivo, our studies show that lincNORS is subject to multiple regulatory inputs, including estrogen signals. Biochemically, this lincRNA fine-tunes cellular sterol/steroid biosynthesis by repressing the expression of multiple pathway components. Mechanistically, the function of lincNORS requires the presence of RALY, an RNA-binding protein recently found to be implicated in cholesterol homeostasis. We also noticed the proximity between this locus and naturally occurring genetic variations highly significant for sterol/steroid-related phenotypes, in particular the age of sexual maturation. An integrative analysis of these variants provided a more formal link between these phenotypes and lincNORS, further strengthening the case for its biological relevance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-020-18411-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505984PMC
September 2020

Genetics of early growth traits.

Hum Mol Genet 2020 09;29(R1):R66-R72

Institute of Biomedical and Clinical Science, University of Exeter Medical School, University of Exeter, Exeter EX2 5DW, UK.

In recent years, genome-wide association studies have shed light on the genetics of early growth and its links with later-life health outcomes. Large-scale datasets and meta-analyses, combined with recently developed analytical methods, have enabled dissection of the maternal and fetal genetic contributions to variation in birth weight. Additionally, longitudinal approaches have shown differences between the genetic contributions to infant, childhood and adult adiposity. In contrast, studies of adult height loci have shown strong associations with early body length and childhood height. Early growth-associated loci provide useful tools for causal analyses: Mendelian randomization (MR) studies have provided evidence that early BMI and height are causally related to a number of adult health outcomes. We advise caution in the design and interpretation of MR studies of birth weight investigating effects of fetal growth on later-life cardiometabolic disease because birth weight is only a crude indicator of fetal growth, and the choice of genetic instrument (maternal or fetal) will greatly influence the interpretation of the results. Most genetic studies of early growth have to date centered on European-ancestry participants and outcomes measured at a single time-point, so key priorities for future studies of early growth genetics are aggregation of large samples of diverse ancestries and longitudinal studies of growth trajectories.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddaa149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530515PMC
September 2020

Type 1 diabetes in Africa: an immunogenetic study in the Amhara of North-West Ethiopia.

Diabetologia 2020 10 23;63(10):2158-2168. Epub 2020 Jul 23.

Centre for Public Health, Institute of Clinical Science, Queen's University Belfast, Grosvenor Road, Belfast, BT12 6BA, UK.

Aims/hypothesis: We aimed to characterise the immunogenic background of insulin-dependent diabetes in a resource-poor rural African community. The study was initiated because reports of low autoantibody prevalence and phenotypic differences from European-origin cases with type 1 diabetes have raised doubts as to the role of autoimmunity in this and similar populations.

Methods: A study of consecutive, unselected cases of recently diagnosed, insulin-dependent diabetes (n = 236, ≤35 years) and control participants (n = 200) was carried out in the ethnic Amhara of rural North-West Ethiopia. We assessed their demographic and socioeconomic characteristics, and measured non-fasting C-peptide, diabetes-associated autoantibodies and HLA-DRB1 alleles. Leveraging genome-wide genotyping, we performed both a principal component analysis and, given the relatively modest sample size, a provisional genome-wide association study. Type 1 diabetes genetic risk scores were calculated to compare their genetic background with known European type 1 diabetes determinants.

Results: Patients presented with stunted growth and low BMI, and were insulin sensitive; only 15.3% had diabetes onset at ≤15 years. C-peptide levels were low but not absent. With clinical diabetes onset at ≤15, 16-25 and 26-35 years, 86.1%, 59.7% and 50.0% were autoantibody positive, respectively. Most had autoantibodies to GAD (GADA) as a single antibody; the prevalence of positivity for autoantibodies to IA-2 (IA-2A) and ZnT8 (ZnT8A) was low in all age groups. Principal component analysis showed that the Amhara genomes were distinct from modern European and other African genomes. HLA-DRB1*03:01 (p = 0.0014) and HLA-DRB1*04 (p = 0.0001) were positively associated with this form of diabetes, while HLA-DRB1*15 was protective (p < 0.0001). The mean type 1 diabetes genetic risk score (derived from European data) was higher in patients than control participants (p = 1.60 × 10). Interestingly, despite the modest sample size, autoantibody-positive patients revealed evidence of association with SNPs in the well-characterised MHC region, already known to explain half of type 1 diabetes heritability in Europeans.

Conclusions/interpretation: The majority of patients with insulin-dependent diabetes in rural North-West Ethiopia have the immunogenetic characteristics of autoimmune type 1 diabetes. Phenotypic differences between type 1 diabetes in rural North-West Ethiopia and the industrialised world remain unexplained.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-020-05229-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476916PMC
October 2020

Genetically Determined Birthweight Associates With Atrial Fibrillation: A Mendelian Randomization Study.

Circ Genom Precis Med 2020 06 27;13(3):e002553. Epub 2020 Apr 27.

Surgery (N.T., R.J., S.M.D.), University of Pennsylvania.

Background: Atrial fibrillation is a common cardiovascular disorder, characterized by irregular electrical activity in the upper chambers of the heart. Both chronic cardiometabolic risk factors and genetics have been shown to contribute to the development of atrial fibrillation. Birthweight has also been associated with risk of atrial fibrillation.

Methods: In the current study, we utilized a genetic approach to study the effect of birthweight on atrial fibrillation. We used 2-sample Mendelian randomization to consider the impact of birthweight on incident atrial fibrillation using summary data from the Early Growth Genetics Consortium GWAS of birthweight and a large biobank-based GWAS of atrial fibrillation.

Results: Using the framework of 2-sample Mendelian randomization, we found that a 1-SD genetic elevation of birthweight was associated with increased risk of atrial fibrillation (odds ratio, 1.27 [95% CI, 1.14-1.41]; =1×10) with sensitivity analyses demonstrating robustness of this result.

Conclusions: Our findings clarify the directionality of the relationship between birthweight and atrial fibrillation, supporting the growing body of evidence that intrauterine growth has a lifelong impact on cardiovascular health.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCGEN.119.002553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299774PMC
June 2020

Genetic Discrimination Between LADA and Childhood-Onset Type 1 Diabetes Within the MHC.

Diabetes Care 2020 02 16;43(2):418-425. Epub 2019 Dec 16.

Department of Immunobiology, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, U.K.

Objective: The MHC region harbors the strongest loci for latent autoimmune diabetes in adults (LADA); however, the strength of association is likely attenuated compared with that for childhood-onset type 1 diabetes. In this study, we recapitulate independent effects in the MHC class I region in a population with type 1 diabetes and then determine whether such conditioning in LADA yields potential genetic discriminators between the two subtypes within this region.

Research Design And Methods: Chromosome 6 was imputed using SNP2HLA, with conditional analysis performed in type 1 diabetes case subjects ( = 1,985) and control subjects ( = 2,219). The same approach was applied to a LADA cohort ( = 1,428) using population-based control subjects ( = 2,850) and in a separate replication cohort (656 type 1 diabetes case, 823 LADA case, and 3,218 control subjects).

Results: The strongest associations in the MHC class II region (rs3957146, β [SE] = 1.44 [0.05]), as well as the independent effect of MHC class I genes, on type 1 diabetes risk, particularly (β [SE] = 1.36 [0.17]), were confirmed. The conditional analysis in LADA versus control subjects showed significant association in the MHC class II region (rs3957146, β [SE] = 1.14 [0.06]); however, we did not observe significant independent effects of MHC class I alleles in LADA.

Conclusions: In LADA, the independent effects of MHC class I observed in type 1 diabetes were not observed after conditioning on the leading MHC class II associations, suggesting that the MHC class I association may be a genetic discriminator between LADA and childhood-onset type 1 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc19-0986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6971787PMC
February 2020

GWAS on longitudinal growth traits reveals different genetic factors influencing infant, child, and adult BMI.

Sci Adv 2019 09 4;5(9):eaaw3095. Epub 2019 Sep 4.

Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, UK.

Early childhood growth patterns are associated with adult health, yet the genetic factors and the developmental stages involved are not fully understood. Here, we combine genome-wide association studies with modeling of longitudinal growth traits to study the genetics of infant and child growth, followed by functional, pathway, genetic correlation, risk score, and colocalization analyses to determine how developmental timings, molecular pathways, and genetic determinants of these traits overlap with those of adult health. We found a robust overlap between the genetics of child and adult body mass index (BMI), with variants associated with adult BMI acting as early as 4 to 6 years old. However, we demonstrated a completely distinct genetic makeup for peak BMI during infancy, influenced by variation at the locus. These findings suggest that different genetic factors control infant and child BMI. In light of the obesity epidemic, these findings are important to inform the timing and targets of prevention strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.aaw3095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904961PMC
September 2019

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

Bone 2020 03 29;132:115175. Epub 2019 Nov 29.

Department of Nutrition and Nutrition Research Institute, University of North Carolina at Chapel Hill, Kannapolis, NC, USA. Electronic address:

Context: Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied.

Objective: We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children.

Methods: We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4-19 years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry.

Results: Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P < 2.8 × 10). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score > 3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P = 4.6 × 10), and between pelvis BMD and rs7000615 at PTK2B (P = 7.4 × 10). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P < 9 × 10).

Conclusions: We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. These findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2019.115175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7120871PMC
March 2020

Associations of autozygosity with a broad range of human phenotypes.

Nat Commun 2019 10 31;10(1):4957. Epub 2019 Oct 31.

Department of Neurology, Brain Centre Rudolf Magnus, University Medical Centre Utrecht, Utrecht University, Utrecht, 3584 CX, The Netherlands.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.4 million individuals, we show that F is significantly associated (p < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F are confirmed within full-sibling pairs, where the variation in F is independent of all environmental confounding.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-12283-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6823371PMC
October 2019

A trans-ancestral meta-analysis of genome-wide association studies reveals loci associated with childhood obesity.

Hum Mol Genet 2019 10;28(19):3327-3338

Unidad de Investigacion Medica en Bioquımica, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico.

Although hundreds of genome-wide association studies-implicated loci have been reported for adult obesity-related traits, less is known about the genetics specific for early-onset obesity and with only a few studies conducted in non-European populations to date. Searching for additional genetic variants associated with childhood obesity, we performed a trans-ancestral meta-analysis of 30 studies consisting of up to 13 005 cases (≥95th percentile of body mass index (BMI) achieved 2-18 years old) and 15 599 controls (consistently <50th percentile of BMI) of European, African, North/South American and East Asian ancestry. Suggestive loci were taken forward for replication in a sample of 1888 cases and 4689 controls from seven cohorts of European and North/South American ancestry. In addition to observing 18 previously implicated BMI or obesity loci, for both early and late onset, we uncovered one completely novel locus in this trans-ancestral analysis (nearest gene, METTL15). The variant was nominally associated with only the European subgroup analysis but had a consistent direction of effect in other ethnicities. We then utilized trans-ancestral Bayesian analysis to narrow down the location of the probable causal variant at each genome-wide significant signal. Of all the fine-mapped loci, we were able to narrow down the causative variant at four known loci to fewer than 10 single nucleotide polymorphisms (SNPs) (FAIM2, GNPDA2, MC4R and SEC16B loci). In conclusion, an ethnically diverse setting has enabled us to both identify an additional pediatric obesity locus and further fine-map existing loci.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddz161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859434PMC
October 2019

Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors.

Nat Genet 2019 05 1;51(5):804-814. Epub 2019 May 1.

Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.

Birth weight variation is influenced by fetal and maternal genetic and non-genetic factors, and has been reproducibly associated with future cardio-metabolic health outcomes. In expanded genome-wide association analyses of own birth weight (n = 321,223) and offspring birth weight (n = 230,069 mothers), we identified 190 independent association signals (129 of which are novel). We used structural equation modeling to decompose the contributions of direct fetal and indirect maternal genetic effects, then applied Mendelian randomization to illuminate causal pathways. For example, both indirect maternal and direct fetal genetic effects drive the observational relationship between lower birth weight and higher later blood pressure: maternal blood pressure-raising alleles reduce offspring birth weight, but only direct fetal effects of these alleles, once inherited, increase later offspring blood pressure. Using maternal birth weight-lowering genotypes to proxy for an adverse intrauterine environment provided no evidence that it causally raises offspring blood pressure, indicating that the inverse birth weight-blood pressure association is attributable to genetic effects, and not to intrauterine programming.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-019-0403-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522365PMC
May 2019

Postmenopausal osteoporotic fracture-associated COLIA1 variant impacts bone accretion in girls.

Bone 2019 04 31;121:221-226. Epub 2019 Jan 31.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America; Department of Genetics, University of Pennsylvania, Philadelphia, PA, United States of America; Center for Spatial and Functional Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, United States of America. Electronic address:

Over the past two decades, a low frequency variant (rs1800012) within the first intron of the type I collagen alpha 1 (COLIA1) gene has been implicated in lower areal BMD (aBMD) and increased risk of osteoporotic fracture. This association is particularly strong in postmenopausal women, in whom net bone loss arises in the context of high bone turnover. High bone turnover also accompanies childhood linear growth; however, the role of rs1800012 in this stage of net bone accretion is less well understood. Thus, we assessed the association between rs1800012 and aBMD and bone mineral content (BMC) Z-scores for the 1/3 distal radius, lumbar spine, total hip, and femoral neck total body less head in the Bone Mineral Density in Childhood Study, a mixed-longitudinal cohort of children and adolescents (total n = 804 girls and 771 boys; n = 19 girls and 22 boys with the TT genotype). Mixed effects modeling, stratified by sex, was used to test for associations between rs1800012 and aBMD or BMC Z-scores and for pubertal stage interactions. Separately, SITAR growth modeling of aBMD and BMC in subjects with longitudinal data reduced the complex longitudinal bone accrual curves into three parameters representing a-size, b-timing, and c-velocity. We tested for differences in these three parameters by rs1800012 genotype using t-tests. Girls with the TT genotype had significantly lower aBMD and BMC Z-scores prior to puberty completion (e.g. spine aBMD-Z P-interaction = 1.0 × 10), but this association was attenuated post-puberty. SITAR models revealed that TT girls began pubertal bone accrual later (b-timing; e.g. total hip BMC, P = 0.03). BMC and aBMD Z-scores also increased across puberty in TT homozygous boys. Our data, along with previous findings in post-menopausal women, suggest that rs1800012 principally affects female bone density during periods of high turnover. Insights into the genetics of bone gain and loss may be masked during the relatively quiescent state in mid-adulthood, and discovery efforts should focus on early and late life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2019.01.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800229PMC
April 2019

Author Correction: Public resources aid diabetes gene discovery.

Nat Genet 2018 12;50(12):1753

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

In the version of this article originally published, the text was incorrect in the first paragraph of the 'Remaining challenges' section. The first two sentences appeared as "Even though this current study substantially increases the number of loci associated with T2D, only approximately 18% of the genetic component of T2D risk is explained by the total complement of genetic variants uncovered genome wide in Mahajan et al.. Interestingly, only a small proportion of that heritability was explained by low-frequency or rare variants (~1.1%), thus potentially indicating that many more of these variants still remain to be characterized in even larger sample sizes." However, they should have read "Even though this current study substantially increases the number of loci associated with T2D, only a proportion of the genetic component of T2D risk is explained by the total complement of genetic variants uncovered genome wide in Mahajan et al.. Interestingly, only a relatively small proportion of that heritability was explained by low-frequency or rare variants, thus potentially indicating that many more of these variants still remain to be characterized in even larger sample sizes." The text has been corrected in the HTML and PDF versions of the paper.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0292-8DOI Listing
December 2018

Public resources aid diabetes gene discovery.

Nat Genet 2018 11;50(11):1499-1500

Center for Spatial and Functional Genomics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-018-0242-5DOI Listing
November 2018

First Genome-Wide Association Study of Latent Autoimmune Diabetes in Adults Reveals Novel Insights Linking Immune and Metabolic Diabetes.

Diabetes Care 2018 11 25;41(11):2396-2403. Epub 2018 Sep 25.

Objective: Latent autoimmune diabetes in adults (LADA) shares clinical features with both type 1 and type 2 diabetes; however, there is ongoing debate regarding the precise definition of LADA. Understanding its genetic basis is one potential strategy to gain insight into appropriate classification of this diabetes subtype.

Research Design And Methods: We performed the first genome-wide association study of LADA in case subjects of European ancestry versus population control subjects ( = 2,634 vs. 5,947) and compared against both case subjects with type 1 diabetes ( = 2,454 vs. 968) and type 2 diabetes ( = 2,779 vs. 10,396).

Results: The leading genetic signals were principally shared with type 1 diabetes, although we observed positive genetic correlations genome-wide with both type 1 and type 2 diabetes. Additionally, we observed a novel independent signal at the known type 1 diabetes locus harboring , encoding a regulator of glycolysis and insulin signaling in type 2 diabetes and inflammation and autophagy in autoimmune disease, as well as an attenuation of key type 1-associated HLA haplotype frequencies in LADA, suggesting that these are factors that distinguish childhood-onset type 1 diabetes from adult autoimmune diabetes.

Conclusions: Our results support the need for further investigations of the genetic factors that distinguish forms of autoimmune diabetes as well as more precise classification strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc18-1032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6196829PMC
November 2018

Relevance of polymorphisms in MC4R and BDNF in short normal stature.

BMC Pediatr 2018 08 22;18(1):278. Epub 2018 Aug 22.

Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: Variation in genes of the leptinergic-melanocortinergic system influence both body weight and height. Because short normal stature (SNS) is characterized by reduced body height, delayed maturation and leanness, allelic variation of genes in this pathway are hypothesized to affect this common condition.

Methods: We analyzed the coding regions of LEP, MC4R, MRAP2 and BDNF in 185 children with SNS (height < 5th percentile) to search for non-synonymous and frameshift variants. For association studies (two-sided χ-tests) population-based data sets (ExAC, EVS and KORA) were used. Cyclic AMP accumulation, cell surface expression, central expression and MAP kinase activation were assayed in vitro to determine the functional implications of identified variants.

Results: We detected eleven variants predicted to be protein-altering, four in MC4R, four in BDNF, and three in MRAP2. No variants were found in LEP. In vitro analysis implied reduced function for the MC4R variant p.Met215Ile. Loss-of-function is contrary to expectations based on obesity studies, and thus does not support that this variant is relevant for SNS. The minor SNP alleles at MC4R p.Val103Ile and BDNF p.Val66Met were nominally associated with SNS.

Conclusion: Taken together, although genes of the leptinergic-melanocortinergic system are important for normal growth, our data do not support the involvement of rare mutations in LEP, MC4R, MRAP2 or BDNF in short normal stature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12887-018-1245-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6106737PMC
August 2018

A Global Perspective of Latent Autoimmune Diabetes in Adults.

Trends Endocrinol Metab 2018 09 23;29(9):638-650. Epub 2018 Jul 23.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA; Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA. Electronic address:

Latent autoimmune diabetes in adults (LADA) is characterized by the presence of islet autoantibodies and initial insulin independence, which can lead to misdiagnosis of type 2 diabetes (T2D). As such, understanding the genetic etiology of LADA could aid in more accurate diagnosis. However, there is ongoing debate regarding the exact definition of LADA, so understanding its impact in different populations when contrasted with type 1 diabetes (T1D) and T2D is one potential strategy to gain insight into its etiology. Unfortunately, the lack of consistent and thorough autoantibody screening around the world has hampered well-powered genetic studies of LADA. This review highlights recent genetic and epidemiological studies of LADA in diverse populations as well as the importance of autoantibody screening in facilitating future research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tem.2018.07.001DOI Listing
September 2018

Physical Activity and Bone Accretion: Isotemporal Modeling and Genetic Interactions.

Med Sci Sports Exerc 2018 05;50(5):977-986

Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: This study aimed to determine if replacing time spent in high- and low-impact physical activity (PA) predicts changes in pediatric bone mineral density (BMD) and content (BMC).

Methods: We analyzed data from the longitudinal Bone Mineral Density in Childhood Study (N = 2337 with up to seven visits). The participants were age 5-19 yr at baseline, 51.2% were female, and 80.6% were nonblack. Spine, total hip, and femoral neck areal BMD and total body less head (TBLH) BMC Z-scores were calculated. Hours per day spent in high- and low-impact PA were self-reported. Standard covariate-adjusted (partition model) and time allocation-sensitive isotemporal substitution modeling frameworks were applied to linear mixed models. Statistical interactions with sex, self-reported ancestry, age, and bone fragility genetic scores (percentage of areal BMD-lowering alleles carried) were tested.

Results: In standard models, high-impact PA was positively associated with bone Z-score at all four skeletal sites (e.g., TBLH-BMC Z-score: beta = 0.05, P = 2.0 × 10), whereas low-impact PA was not associated with any of the bone Z-scores. In isotemporal substitution models, replacing 1 h·d of low- for high-impact PA was associated with higher bone Z-scores (e.g., TBLH-BMC Z-score: beta = 0.06, P = 2.9 × 10). Conversely, replacing 1 h·d of high- for low-impact PA was associated with lower bone Z-scores (e.g., TBLH-BMC Z-score: beta = -0.06, P = 2.9 × 10). The substitution associations were similar for each sex and ancestry group, and for those with higher and lower genetic scores for bone fragility (P-interactions > 0.05), but increased in strength among the older adolescents (P-age interactions < 0.05).

Conclusions: Time-sensitive models suggest that replacing low-impact PA for high-impact PA would be beneficial for the growing skeleton in the majority of children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1249/MSS.0000000000001520DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5899052PMC
May 2018

Multidimensional Bone Density Phenotyping Reveals New Insights Into Genetic Regulation of the Pediatric Skeleton.

J Bone Miner Res 2018 05 30;33(5):812-821. Epub 2018 Mar 30.

Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Osteoporosis is a complex disease with developmental origins. It is therefore important to understand the genetic contribution to pediatric areal bone mineral density (aBMD). Individual skeletal site phenotyping has been primarily used to identify pediatric aBMD loci. However, this approach is limited because there is a degree of aBMD discordance across skeletal sites. We therefore applied a novel multidimensional phenotyping approach to further understand the genetic regulation of pediatric aBMD. Our sample comprised a prospective, longitudinal cohort of 1293 children of European ancestry (52% female; up to seven annual measurements). Principal components analysis was applied to dual-energy X-ray absorptiometry-derived aBMD Z-scores for total hip, femoral neck, spine, and distal radius to generate multidimensional aBMD phenotypes (ie, principal component scores). We tested the association between a genetic score (percentage of bone lowering alleles at 63 loci) and each principal component. We also performed a genomewide association study (GWAS) using the multiethnic baseline data (n = 1885) to identify novel loci associated with these principal components. The first component (PC1) reflected a concordant phenotypic model of the skeleton (eg, higher loading score = higher BMD across all sites). In contrast, PC2 was discordant for distal radius versus spine and hip aBMD, and PC3 was discordant for spine versus distal radius and hip aBMD. The genetic score was associated with PC1 (beta = -0.05, p = 3.9 × 10 ), but was not associated with discordant PC2 or PC3. Our GWAS discovered variation near CPED1 that associated with PC2 (rs67991850, p = 2.5 × 10 ) and near RAB11FIP5 (rs58649746, p = 4.8 × 10 ) that associated with PC3. In conclusion, an established bone fragility genetic summary score was associated with a concordant skeletal phenotype, but not discordant skeletal phenotypes. Novel associations were observed for the discordant multidimensional skeletal phenotypes that provide new biological insights into the developing skeleton. © 2017 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473448PMC
May 2018

Genetically Determined Later Puberty Impacts Lowered Bone Mineral Density in Childhood and Adulthood.

J Bone Miner Res 2018 03 17;33(3):430-436. Epub 2017 Nov 17.

Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Later puberty associates with lower areal bone mineral density (aBMD), and both are risk factors for osteoporosis. However, the association between puberty timing-associated genetic variants and aBMD during development, and the causal relationship between puberty timing and aBMD, remain uncharacterized. We constructed sex-specific polygenic risk scores (GRS) consisting of 333 genetic variants associated with later puberty in European-descent children in the Bone Mineral Density in Childhood Study (BMDCS), consisting of a longitudinal cohort with up to seven assessments (n = 933) and a cross-sectional cohort (n = 486). These GRS were tested for associations with age- and sex-specific aBMD Z-scores at the lumbar spine (LS), femoral neck (FN), total hip, and distal radius, accounting for clinical covariates using sex-stratified linear mixed models. The causal relationship between puberty timing and aBMD was tested in the BMDCS and in publicly available adult data (GEFOS consortium) using two-sample Mendelian randomization (MR). The puberty-delaying GRS was associated with later puberty and lower LS-aBMD in the BMDCS in both sexes (combined beta ± SE = -0.078 ± 0.024; p = 0.0010). In the MR framework, the puberty-delaying genetic instrument also supported a causal association with lower LS-aBMD and FN-aBMD in adults of both sexes. Our results suggest that pubertal timing is causal for diminished aBMD in a skeletal site- and sex-specific manner that tracks throughout life, potentially impacting later risk for osteoporosis, which should be tested in future studies. © 2017 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5839967PMC
March 2018

Low-Frequency Synonymous Coding Variation in CYP2R1 Has Large Effects on Vitamin D Levels and Risk of Multiple Sclerosis.

Am J Hum Genet 2017 Aug 27;101(2):227-238. Epub 2017 Jul 27.

Department of Internal Medicine, Erasmus Medical Center, Rotterdam 3015 GE, the Netherlands.

Vitamin D insufficiency is common, correctable, and influenced by genetic factors, and it has been associated with risk of several diseases. We sought to identify low-frequency genetic variants that strongly increase the risk of vitamin D insufficiency and tested their effect on risk of multiple sclerosis, a disease influenced by low vitamin D concentrations. We used whole-genome sequencing data from 2,619 individuals through the UK10K program and deep-imputation data from 39,655 individuals genotyped genome-wide. Meta-analysis of the summary statistics from 19 cohorts identified in CYP2R1 the low-frequency (minor allele frequency = 2.5%) synonymous coding variant g.14900931G>A (p.Asp120Asp) (rs117913124[A]), which conferred a large effect on 25-hydroxyvitamin D (25OHD) levels (-0.43 SD of standardized natural log-transformed 25OHD per A allele; p value = 1.5 × 10). The effect on 25OHD was four times larger and independent of the effect of a previously described common variant near CYP2R1. By analyzing 8,711 individuals, we showed that heterozygote carriers of this low-frequency variant have an increased risk of vitamin D insufficiency (odds ratio [OR] = 2.2, 95% confidence interval [CI] = 1.78-2.78, p = 1.26 × 10). Individuals carrying one copy of this variant also had increased odds of multiple sclerosis (OR = 1.4, 95% CI = 1.19-1.64, p = 2.63 × 10) in a sample of 5,927 case and 5,599 control subjects. In conclusion, we describe a low-frequency CYP2R1 coding variant that exerts the largest effect upon 25OHD levels identified to date in the general European population and implicates vitamin D in the etiology of multiple sclerosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2017.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5544392PMC
August 2017

Association Between Linear Growth and Bone Accrual in a Diverse Cohort of Children and Adolescents.

JAMA Pediatr 2017 09 5;171(9):e171769. Epub 2017 Sep 5.

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Importance: Prevention of osteoporosis in adulthood begins with optimizing bone health in early life. The longitudinal association between growth and bone accretion during childhood is not fully understood.

Objectives: To assess the acquisition of whole-body (WB) and skeletal site-specific bone mineral content (BMC) relative to linear growth in a healthy, diverse, longitudinal cohort of children, adolescents, and young adults and to test for differences related to sex and African American race.

Design, Setting, And Participants: This investigation was a mixed longitudinal study with annual assessments for up to 7 years at 5 US clinical centers. Participants were healthy children, adolescents, and young adults. The study dates were July 2002 through March 2010. The dates of the analysis were June through December 2016.

Main Outcomes And Measures: Anthropometrics, BMC, and body composition via dual-energy x-ray absorptiometry. The superimposition by translation and rotation (SITAR) analysis method was used to define the mean trajectories for height, WB lean soft tissue, appendicular lean soft tissue, and WB and skeletal site-specific BMC acquisition and to measure the age and magnitude of peak velocity for each parameter. The SITAR modeling was performed separately by sex and self-reported race.

Results: Among 2014 healthy children, adolescents, and young adults (1022 [50.7%] female and 479 [23.8%] African American) aged 5 to 19 years at study entry, the mean age of peak height velocity was 13.1 years (95% CI, 13.0-13.2 years) in African American boys vs 13.4 years (95% CI, 13.3-13.4 years) in non-African American boys (difference, -0.3 years; 95% CI, -0.4 to -0.1 years) and 11.0 years (95% CI, 10.8-11.1 years) in African American girls vs 11.6 years (95% CI, 11.5-11.6 years) in non-African American girls (difference, -0.6 years; 95% CI, -0.7 to -0.5 years). Age of peak acquisition of WB BMC was 14.0 years (95% CI, 13.8-14.1 years) in African American boys vs 14.0 years (95% CI, 13.9-14.1 years) in non-African American boys (difference, -0.0 years; 95% CI, -0.2 to 0.2 years) and 12.1 years (95% CI, 12.0-12.3 years) in African American girls vs 12.4 years (95% CI, 12.3-12.5 years) in non-African American girls (difference, -0.3 years; 95% CI, -0.4 to -0.1 years). At age 7 years, children had acquired 69.5% to 74.5% of maximal observed height but only 29.6% to 38.1% of maximal observed WB BMC. Adolescents gained 32.7% to 35.8% of maximal observed WB BMC during the 2 years before and 2 years after peak height velocity. Another 6.9% to 10.7% of maximal observed WB BMC occurred after linear growth had ceased. In the group at highest risk for fracture, non-African American boys, peak fracture incidence occurred approximately 1 year before peak height velocity.

Conclusions And Relevance: In this longitudinal study, height gains substantially outpaced gains in BMC during childhood, which could contribute to fracture risk. A significant proportion of bone is accrued after adult height is achieved. Therefore, late adolescence represents a potentially underrecognized window of opportunity to optimize bone mass.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamapediatrics.2017.1769DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632753PMC
September 2017

Relative contribution of type 1 and type 2 diabetes loci to the genetic etiology of adult-onset, non-insulin-requiring autoimmune diabetes.

BMC Med 2017 04 25;15(1):88. Epub 2017 Apr 25.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Background: In adulthood, autoimmune diabetes can present as non-insulin-requiring diabetes, termed as 'latent autoimmune diabetes in adults' (LADA). In this study, we investigated established type 1 diabetes (T1D) and type 2 diabetes (T2D) genetic loci in a large cohort of LADA cases to assess where LADA is situated relative to these two well-characterized, classic forms of diabetes.

Methods: We tested the association of T1D and T2D GWAS-implicated loci in 978 LADA cases and 1057 non-diabetic controls of European ancestry using a linear mixed model. We then compared the associations of T1D and T2D loci between LADA and T1D and T2D cases, respectively. We quantified the difference in genetic risk between each given disease at each locus, and also calculated genetic risk scores to quantify how genetic liability to T1D and T2D distinguished LADA cases from controls.

Results: Overall, our results showed that LADA is genetically more similar to T1D, with the exception of an association at the T2D HNF1A locus. Several T1D loci were associated with LADA, including the major histocompatibility complex region, as well as at PTPN22, SH2B3, and INS. Contrary to previous studies, the key T2D risk allele at TCF7L2 (rs7903146-T) had a significantly lower frequency in LADA cases, suggesting that this locus does not play a role in LADA etiology. When constrained on antibody status, the similarity between LADA and T1D became more apparent; however, the HNF1A and TCF7L2 observations persisted.

Conclusion: LADA is genetically closer to T1D than T2D, although the genetic load of T1D risk alleles is less than childhood-onset T1D, particularly at the major histocompatibility complex region, potentially accounting for the later disease onset. Our results show that the genetic spectrum of T1D extends into adult-onset diabetes, where it can clinically masquerade as T2D. Furthermore, T2D genetic risk plays a small role in LADA, with a degree of evidence for the HNF1A locus, highlighting the potential for genetic risk scores to contribute towards defining diabetes subtypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12916-017-0846-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5404312PMC
April 2017
-->