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Chipping away the 'missing heritability': GIANT steps forward in the molecular elucidation of obesity - but still lots to go.

ABSTRACT: Although heritability of human body weight is assumed to be high, only a small fraction of the variance can as yet be attributed to molecular genetic factors. Single monogenic forms of obesity have been identified. Functionally relevant coding mutations in the melanocortin-4 receptor gene occur in 1-6% of extremely obese children and adolescents and thus represent the most common major gene effect. Genome-wide association studies (GWAS) had previously identified 14 obesity loci with genome-wide significant (p < 5 x 10-8) associations. Many of the respective genes are expressed in the central nervous system. The GIANT (Genetic Investigation of ANtropometric Traits) Consortium has now performed a meta-analysis of GWAS data based on 123,865 individuals of European ancestry followed by confirmatory analyses for the 42 best independent loci in up to 125,931 independent individuals (Speliotes et al: Association analyses of 249,796 individuals reveal eighteen new loci associated with body mass index. Nature Genetics; epub October 2010 [1]). Apart from confirming the 14 known loci, 18 novel BMI-associated loci (p < 5 x 10-8) were identified. Several of the new loci point to genes involved in key hypothalamic pathways of energy balance. The identified variants mostly have small to very small effect sizes; only 1-2% of the BMI variance is explained. Currently, a consensus explanation for this 'missing heritability' in complex diseases has not yet emerged.

SUBMITTER: Hebebrand J

PROVIDER: S-EPMC6452141 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Chipping away the 'missing heritability': GIANT steps forward in the molecular elucidation of obesity - but still lots to go.

Hebebrand Johannes J Volckmar Anna-Lena AL Knoll Nadja N Hinney Anke A

Obesity facts 20101015 5

Although heritability of human body weight is assumed to be high, only a small fraction of the variance can as yet be attributed to molecular genetic factors. Single monogenic forms of obesity have been identified. Functionally relevant coding mutations in the melanocortin-4 receptor gene occur in 1-6% of extremely obese children and adolescents and thus represent the most common major gene effect. Genome-wide association studies (GWAS) had previously identified 14 obesity loci with genome-wide ...[more]

PMID: 20975295

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Project description:Background: Opportunistic screening for individuals aged ?30 years at all levels of healthcare for early detection of diabetes mellitus (DM) and hypertension (HTN) is an integral strategy under the national program to control non-communicable diseases. There has been no systematic assessment of the screening process in primary care settings since its launch. The objective was to determine the number and proportion eligible for screening, number screened, diagnosed and treated for DM and HTN among persons aged ?30 years in two selected primary health centres (PHCs) in Dakshina Kannada district, Karnataka, India during March-May 2019 and to explore the enablers and barriers in the implementation of screening from the perspective of the health care providers (HCPs) and beneficiaries . Methods: This was a sequential explanatory mixed-methods study with a quantitative (cohort design) and a descriptive qualitative component (in-depth interviews and focus group discussions) with HCPs and persons seeking care. Those that were not known DM/HTN and not screened for DM/HTN in one year were used to estimate persons eligible for screening. Results: Of 2697 persons, 512 (19%) were eligible for DM screening, 401 (78%) were screened; 88/401 (22%) were diagnosed and 67/88 (76%) were initiated on treatment. Of 2697, 337 (13%) were eligible for HTN screening, 327 (97%) were screened, 55 (17%) were diagnosed with HTN; of those diagnosed, 44/55 (80%) were initiated on treatment. The documentation changes helped in identifying the eligible population. Patient willingness to undergo screening and recognition of relevance of screening were screening enablers. Overworked staff, logistical and documentation issues, inadequate training were the barriers. Conclusion: Nearly 19% were eligible for DM screening and 13% were eligible for HTN screening. The yield of screening was high. We noted several enablers and barriers. The barriers require urgent attention to reduce the gaps in delivery and uptake of services.

Project description:Recent work has shown that much of the missing heritability of complex traits can be resolved by estimates of heritability explained by all genotyped SNPs. However, it is currently unknown how much heritability is missing due to poor tagging or additional causal variants at known GWAS loci. Here, we use variance components to quantify the heritability explained by all SNPs at known GWAS loci in nine diseases from WTCCC1 and WTCCC2. After accounting for expectation, we observed all SNPs at known GWAS loci to explain 1.29 x more heritability than GWAS-associated SNPs on average (P=3.3 x 10??). For some diseases, this increase was individually significant: 2.07 x for Multiple Sclerosis (MS) (P=6.5 x 10??) and 1.48 x for Crohn's Disease (CD) (P = 1.3 x 10?³); all analyses of autoimmune diseases excluded the well-studied MHC region. Additionally, we found that GWAS loci from other related traits also explained significant heritability. The union of all autoimmune disease loci explained 7.15 x more MS heritability than known MS SNPs (P < 1.0 x 10?¹? and 2.20 x more CD heritability than known CD SNPs (P = 6.1 x 10??), with an analogous increase for all autoimmune diseases analyzed. We also observed significant increases in an analysis of > 20,000 Rheumatoid Arthritis (RA) samples typed on ImmunoChip, with 2.37 x more heritability from all SNPs at GWAS loci (P = 2.3 x 10??) and 5.33 x more heritability from all autoimmune disease loci (P < 1 x 10?¹? compared to known RA SNPs (including those identified in this cohort). Our methods adjust for LD between SNPs, which can bias standard estimates of heritability from SNPs even if all causal variants are typed. By comparing adjusted estimates, we hypothesize that the genome-wide distribution of causal variants is enriched for low-frequency alleles, but that causal variants at known GWAS loci are skewed towards common alleles. These findings have important ramifications for fine-mapping study design and our understanding of complex disease architecture.

Dataset Information

Chipping away the 'missing heritability': GIANT steps forward in the molecular elucidation of obesity - but still lots to go.

Publications

Chipping away the 'missing heritability': GIANT steps forward in the molecular elucidation of obesity - but still lots to go.

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