Guidelines for community-led multiple use water services: evidence from rural South Africa

The African Water Facility, together with the Water Research Commission, South Africa, as its implementing agent, supported the demonstration project Operationalizing community-led Multiple Use water Services (MUS) in South Africa. As knowledge broker and research partner in this project, the International Water Management Institute (IWMI) analyzed processes and impacts at the local level, where the nongovernmental organization Tsogang Water and Sanitation demonstrated community-led MUS in six diverse rural communities in two of the poorest districts of South Africa, Sekhukhune and Vhembe districts - Ga Mokgotho, Ga Moela and Phiring in the Sekhukhune District Municipality, and Tshakhuma, Khalavha and Ha Gumbu in Vhembe District Municipality. In conventional water infrastructure projects, external state or non-state agencies plan, diagnose, design and prioritize solutions, mobilize funding, and implement the procurement of materials, recruitment of workers and construction. However, this MUS project facilitated decision-making by communities, and provided technical and institutional advice and capacity development. Based on IWMI’s evidence, tools and manuals, the project team organized learning alliances and policy dialogues from municipal to national level on the replication of community-led MUS by water services authorities; government departments of water, agriculture, and others; employment generation programs; climate and disaster management; and corporate social responsibility initiatives. This working paper synthesizes the lessons learned about the six steps of the community-led MUS process in all six communities. The step-wise process appeared to be welcome and effective across the board. The duration of the process and the costs of facilitation, technical and institutional capacity development, and engineering advice and quality control were comparable to conventional approaches. However, the respective responsibilities of the government and communities, also in longer-term co-management arrangements, depended on the type of infrastructure. Some communities were supported to improve their communal self supply systems. In other communities, the process enabled an extension of the reticulation of borehole systems owned, operated and maintained by municipalities. Almost all households used water supplies at homesteads for multiple purposes, underscoring synergies in cross-sectoral collaboration between the water, sanitation and hygiene (WASH) and irrigation sectors

Process and benefits of community-led multiple use water services: comparing two communities in South Africa

The African Water Facility, together with the Water Research Commission, South Africa, as its implementing agent, supported the demonstration project Operationalizing community-led Multiple Use water Services (MUS) in South Africa. As knowledge broker and research partner in this project, the International Water Management Institute (IWMI) analyzed processes and impacts at the local level, where the nongovernmental organization Tsogang Water and Sanitation demonstrated community-led MUS in six diverse rural communities in two of the poorest districts of South Africa, Sekhukhune and Vhembe districts - Ga Mokgotho, Ga Moela and Phiring in the Sekhukhune District Municipality, and Tshakhuma, Khalavha and Ha Gumbu in Vhembe District Municipality. In conventional water infrastructure projects, external state and non-state agencies plan, diagnose, design and prioritize solutions, mobilize funding, and implement the procurement of materials, recruitment of workers and construction. However, this MUS project facilitated decision-making by communities, and provided technical and institutional advice and capacity development. Based on IWMI’s evidence, tools and manuals, the project team organized learning alliances and policy dialogues from municipal to national level on the replication of community-led MUS by water services authorities; government departments of water, agriculture, and others; employment generation programs; climate and disaster management; and corporate social responsibility initiatives. This working paper reports on the local findings of Ga Mokgotho and Ga Moela villages, which had completed construction works. The paper presents an in-depth analysis from the preproject situation to each of the steps of the participatory process, and highlights the resulting benefits of more water, more reliable and sustainable supplies, and multiple benefits, including a 60% and 76% increase in the value of irrigated produce in Ga Mokgotho and Ga Moela, respectively. Women were the sole irrigation manager in 68% and 60% of the households in Ga Mokgotho and Ga Moela, respectively. The user satisfaction survey highlighted communities’ unanimous preference of the participatory process, capacity development and ownership compared to conventional approaches

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.

Mutations in GABRB3

Objective: To examine the role of mutations in GABRB3 encoding the b3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands frommultiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy withmyoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant beta(3), together with alpha(5) and gamma(2s) subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism

Recurrent candidiasis and early-onset gastric cancer in a patient with a genetically defined partial MYD88 defect

Gastric cancer is caused by both genetic and environmental factors. A woman who suffered from recurrent candidiasis throughout her life developed diffuse-type gastric cancer at the age of 23 years. Using whole-exome sequencing we identified a germline homozygous missense variant in MYD88. Immunological assays on peripheral blood mononuclear cells revealed an impaired immune response upon stimulation with Candida albicans, characterized by a defective production of the cytokine interleukin-17. Our data suggest that a genetic defect in MYD88 results in an impaired immune response and may increase gastric cancer risk

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Throug

Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function

In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P = 5.6 × 10−9) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 × 10−4-2.2 × 10−7. Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in genera

Genome-wide association and functional follow-up reveals new loci for kidney function

Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genome-wide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 × 10−8): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms