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Background: Estimating relatedness is an important step for many genetic study designs. A variety of methods for estimating coefficients of pairwise relatedness from genotype data have been proposed. Both the kinship coefficient φ and the fraternity coefficient ψ for all pairs of individuals are of interest. However, when dealing with low-depth sequencing or imputation data, individual level genotypes cannot be confidently called. To ignore such uncertainty is known to result in biased estimates. Accordingly, methods have recently been developed to estimate kinship from uncertain genotypes. Results: We present new method-of-moment estimators of both the coefficients φ and ψ calculated directly from genotype likelihoods. We have simulated low-depth genetic data for a sample of individuals with extensive relatedness by using the complex pedigree of the known genetic isolates of Cilento in South Italy. Through this simulation, we explore the behaviour of our estimators, demonstrate their properties, and show advantages over alternative methods. A demonstration of our method is given for a sample of 150 French individuals with down-sampled sequencing data. Conclusions: We find that our method can provide accurate relatedness estimates whilst holding advantages over existing methods in terms of robustness, independence from external software, and required computation time. The method presented in this paper is referred to as LowKi (Low-depth Kinship) and has been made available in an R package (https://github.com/genostats/LowKi). [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxias (SCAs) are a heterogeneous group of autosomal-dominant neurodegenerative disorders involving the cerebellum and 23 different genes. We mapped SCA38 to a 56 Mb region on chromosome 6p in a SCA-affected Italian family by whole-genome linkage analysis. Targeted resequencing identified a single missense mutation (c.689G>T [p.Gly230Val]) in ELOVL5. Mutation screening of 456 independent SCA-affected individuals identified the same mutation in two further unrelated Italian families. Haplotyping showed that at least two of the three families shared a common ancestor. One further missense variant (c.214C>G [p.Leu72Val]) was found in a French family. Both missense changes affect conserved amino acids, are predicted to be damaging by multiple bioinformatics tools, and were not identified in ethnically matched controls or within variant databases. ELOVL5 encodes an elongase involved in the synthesis of polyunsaturated fatty acids of the ω3 and ω6 series. Arachidonic acid and docosahexaenoic acid, two final products of the enzyme, were reduced in the serum of affected individuals. Immunohistochemistry on control mice and human brain demonstrated high levels in Purkinje cells. In transfection experiments, subcellular localization of altered ELOVL5 showed a perinuclear distribution with a signal increase in the Golgi compartment, whereas the wild-type showed a widespread signal in the endoplasmic reticulum. SCA38 and SCA34 are examples of SCAs due to mutations in elongase-encoding genes, emphasizing the importance of fatty-acid metabolism in neurological diseases., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

The discovery of the genetic factors implicated in the predisposition to complex diseases may greatly profit from genetic studies in isolated populations. In this perspective, we performed a genome-wide scan using 507 microsatellite markers, with an average interval size of 7.6 cM, on a sample of 88 nuclear families with at least two affected sibs with bipolar disorder recruited in the Sardinian population. An initial analysis yielded non-parametric linkage exceeding 3.4 with P-values <0.0003 at two adjacent markers, D1S206 and D1S435 in the 1p22-p21 chromosomal region. Moreover, positive linkage ranging between 2.0 and 3.0 was obtained for other loci in several cases in regions that have already been linked to predisposition to bipolar disorder, such as 5p15.33, 8q24.13, and 11q14.3. A subsequent analysis of the 1p22-p21 region using the same set of families and a dense panel of 20 new microsatellite markers, spaced at 1.2 cM on average, reinforced the finding of suggestive linkage for this region. Interestingly, NPL values above 2.1 and P-values <0.02 were obtained for a cluster of 10 markers comprising D1S435. Thus, this study suggests that the 1p22-p21 region may contain a new locus participating to the genetic susceptibility to bipolar disorder and reproduces positive linkage for several other loci already implicated in this pathology. Since the Sardinian population presents a peculiar genetic homogeneity, these results may pave the way to further studies for replication in this population contributing to the rapid discovery of the genetic factors predisposing to bipolar disorder., ((c) 2010 Wiley-Liss, Inc.)