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Little is known about adult siblings of individuals with autism. We report on cognitive, social and mental health outcomes in 87 adult siblings (mean age 39 years). When younger all had been assessed either as being 'unaffected' by autism (n = 69) or as meeting criteria for the 'Broader Autism Phenotype' (BAP, n = 18). As adults, all scored within the average range on tests of intelligence, numeracy and literacy. 'Unaffected' siblings were functioning well in terms of jobs, independence and social relationships. Levels of social relationships and employment were significantly lower in the BAP group; autism traits and mental health problems were significantly higher. The data suggest that the 'broader autism phenotype' is a meaningful concept but more sensitive diagnostic measures are required. Electronic supplementary material The online version of this article (doi:10.1007/s10803-014-2224-5) contains supplementary material, which is available to authorized users., Author(s): Patricia Howlin[sup.1] [sup.2] [sup.6] , Philippa Moss[sup.1] [sup.5] , Sarah Savage[sup.1] [sup.3] , Patrick Bolton[sup.4] , Michael Rutter[sup.4] Author Affiliations: (1) Institute of Psychiatry, King's College, London, UK (2) [...]

We analyzed the whole-genome sequences of a family of four, consisting of two siblings and their parents. Family-based sequencing allowed us to delineate recombination sites precisely, identify 70% of the sequencing errors (resulting in >99.999% accuracy), and identify very rare single-nucleotide polymorphisms. We also directly estimated a human intergeneration mutation rate of ~1.1 x [10.sup.-8] per position per haploid genome. Both offspring in this family have two recessive disorders: Miller syndrome, for which the gene was concurrently identified, and primary ciliary dyskinesia, for which causative genes have been previously identified. Fatally-based genome analysis enabled us to narrow the candidate genes for both of these Mendelian disorders to only four. Our results demonstrate the value of complete genome sequencing in families. doi: 10.1126/science.1186802

The result of the genetic linkage study undertaken for the tourette disorder (TD) is presented. This study analyzed 238 nuclear families yielding 304 independent sibling pairs and 18 separate multigenerational families for a total of 2,040 individuals. Analyses revealed strong evidence of linkage for a region of chromosome 2p.

A study to know the most efficient study designs for test of genetic association using sibship data and unrelated cases and control is presented. The findings of the study will be helpful for researchers designing and analyzing complex disease-association studies and will facilitate genotyping resource allocation.

Two new procedures have been developed using data from siblings to test both linkage and association with quantitative traits. Both biallelic and multiallelic loci can be accommodated. One procedure involves mixed-effects analysis of variance, while the other is permutation-based. Power studies have been performed to evaluate the tests' relative power under various circumstances.

It is proposed that multipoint methods for classification of pairs in a sib-pair genome be based on a Markov-process model of allele sharing on chromosomes. Results of sib-pair linkage studies might be less valid if a substantial number of putative sib pairs are not in fact sib pairs. Such methods will be used in a coming version of the S.A.G.E. computer software package.

Three generalized constraint methods have been proposed. They were evaluated using simulated data. Results compare the power of methods with and without covariates for a single-gene model with age-dependent onset and for quantitative and qualitative gene-gene and gene-environment interaction models. Covariates can improve ability to detect linkage and can be very valuable when there are qualitative gene-environment interactions. The best approach usually is to assume no dominance variance exists and to get constrained estimates for covariate models under the assumption. Covariate models have been developed in the past as an extension to affected sib-pair methods in which covariate effects are jointly estimated with degree of excess allele sharing. The models can estimate differences in sib-pair allele sharing associated with measurable genes or environment. When an affected sib-pair model is generalized to allow for covariates that have an effect on allele sharing, new constraints and methods are needed.

More evidence has been found for the power of LOD scores versus nonparametric methods. Genetic analysis of diseases where the underlying model is not known, model-free methods, among them affected sib pair (ASP) tests, are often preferred over LOD-score methods, though LOD-score methods under the correct or even nearly correct model are more powerful than ASP tests. Whether or not certain models do set up a situation in which ASP tests are more powerful than LOD scores has been investigated. Sl analysis performed twice and corrected for the type I-error increase coming from multiple testing gives almost as much linkage information as an analysis under the correct 2L model does and is more powerful than the NPL method or the ASP method. Even for complex genetic models, the most important condition for linkage analysis is that the assumed mode of inheritance (MOI) at the disease locus tested is approximately correct, not that the inheritance of the disease itself is specified correctly.

A simulation study has been made of effects of assignment of prior identity-by-descent probabilities to sib pairs in covariance-structure modeling of a quantitative-trait locus. The sib pairs are unselected. Sib-pair selection strategies intended for identification of the most informative sib pairs for the purpose of detecting a quantitative-trait locus (QTL) lead to a missing-data problem in genetic covariance-structure modeling of QTL effects. A proposed solution to the problem is assigning prior identity-by-descent (IBD probabilities to the unselected sib pairs. This has been investigated with two maximum-likelihood )approaches to estimation considered. Assignment of prior IBD probabilities brings serious estimation bias in the pi-hat approach. The null distribution of the log-likelihood ratio does not follow the expected null distribution in the pi-hat approach after selection. In the IBD mixture approach, the null distribution is not in agreement with expected results.

Combined association sib-pair and linkage analysis has been carried out for quantitative traits. Extending maximum-likelihood variance-components procedures currently used for mapping quantitative-trait loci in sib pairs in order to allow for a simultaneous test of allelic association has been suggested. Modeling of the allelic means for a test of association is involved, as is modeling at the same time of the sib-pair covariance structure to test linkage. By partitioning the mean effect of a locus into within- and between-sibship components it controls for invalid association made on the basis of population admixture and stratification. Simulations of models of real and unfounded association are used to show the value of the method.

A discordant sibship test using data of all affected and unaffected siblings and suitable for linkage testing and linkage-disequilibrium testing is introduced. The sibship disequilibrium test (SDT) requires no parental data, but at least one affected sibling and one unaffected sibling are needed, and the test can be more powerful than the transmission/disequilibrium test (TDT) for testing linkage disequilibrium especially for disease prevalence.

An extension of one of three recently developed family-based tests of association and linkage using unaffected siblings as surrogates for untyped parents is proposed. The four tests are then compared using as an example the application to a complex disease for both biallelic and multiallelic markers and for sibships of varying sizes, then looking at availability of some parental data.

Planning for the use of sibs, parents, and unrelated controls for finding associations of disease with genetic markers is discussed with methods of computing sample size and power. Misleading associations can be avoided by using parents of disease cases as controls, but they may not be available unless the disease in an early-onset one, while sib controls may be easier to find.

The maximum-likelihood-binomial (MLB) method has been extended to multipoint linkage analysis. The general outline of hidden Markov models is used. A large simulations study has been carried out to study power of robustness of the MLB method in multipoint analysis of varying affected-sibship samples.. The method is based on the binomial distribution of parental marker alleles in affected offspring. The MLB method is compared to the maximum-likelihood-score (MLS) method as used in MAPMAKER/SIBS.

Results of genomewide linkage studies of type 1 diabetes or insulin-dependent diabetes mellitus (IDDM) indicate that in mapping of genes for common multifactorial diseases, analysis of both affected and unaffected siblings is valuable. Both predisposing and nonpredisposing alleles should be anticipated. The studies show that several unlinked susceptibility loci can explain clustering of the disease in families. One locus maps to chromosome 11p13. After 707 affected sib pairs were analyzed a peak multipoint maximum LOD score was found to be 2.7 with linkage over a 15-cM region. To fine map the locus for structural analysis of positional candidate genes was a challenge. Analysis of another 1,702 families have support for negative transmission of D11S1917 (ital) allele 3 to affected offspring and transmission to unaffected siblings.

Blood infection levels of Plasmodium falciparum, an organism that causes malaria in humans, are linked to chromosome 5q31-q33. The existence of complex genetic factors that control P. falciparum blood infection levels has been demonstrated through study of an urban population in Burkina Faso. From 34 families, 153 siblings were subjected to sib-pair linkage analyses between blood infection levels and chromosome 5q31-q33. Linkage of parasitemia to D5S393 and to D5S658 was found.

A much-used measure of familial aggregation is the sibling recurrence-risk ratio or lambda sub S. It is defined as the ratio of risk of disease manifestation, given a sibling's being affected, vs prevalence of the disease in the overall population. The ratio lambda sub S can be greatly inflated because of misunderstanding of the original definition and of ascertainment bias and of overreporting. Like segregation analysis, the estimation of lambda sub S is likely to be affected by ascertainment bias. It should be estimated with great care. If it is used for discrimination between different genetic models, for exclusion mapping and for association studies even more care should be taken.

Nonparametric analysis of affected sib pairs or other small sets of affected relatives provides a simple, robust method of linkage analysis. The shape of the constraint set for identity-by-descent (IBD) probabilities for sibs is related to the robustness of the affected-sib-pair tests. In addition, minmax tests are available that are more robust than the tests currently in use. The minmax tests' robustness is supported by asymptotic-power calculations.

A test statistic, the quantitive LOD (QLOD) score can be used for the testing of both exclusion and linkage of quantitative-trait loci in randomly selected human sibships. The boundary values of 3 for linkage and -2 for exclusion can be used for the score. Sample sizes needed have been investigated.

Several family-based tests of association have been developed using discordant sib pairs (DSPs), those in which one sib is affected with a disease and the other is not. The tests are based on statistics that compare counts of alleles or genotypes or that test for symmetry in tables of genotypes or alleles. A permutation framework was used to assess the significance of the statistics obtained. For late-onset diseases methods that require genotypes on affected persons and their parents may not be suitable. The properties of the DSP-based tests have been compared by computer simulations. An application to Alzheimer's disease and the apolipoprotein E (apoE) polymorphism is illustrative. The discordant-alleles test seems to be the most powerful among those considered.

A method has been developed to overcome a problem that comes up in some methods of studying genetic aspects of complex diseases. It makes possible application of the transmission/disequilibrium test (TDT) using marker data from unaffected siblings instead of from parents and is called the 'sib TDR' or 'S-TDR' method. All data may be used together in an overall TDT type of procedure to test for linkage in the presence of association. Linkage analysis with genetic markers has been useful in the localizing genes for many monogenic human diseases. In studies of complex diseases, however, tests that depend on linkage disequilibrium, the presence of association and linkage at the same time, are often more useful than those that rely on linkage only. The advantage can be seen by TDT, which requires data, that is, marker genotypes, for affected individuals and their parents. For some diseases parent data may not be available. Study of diseases of late onset and of those associated with aging may be advanced using extension of the TDT.

A comparison of physiological reactions, affect and interpersonal responses between siblings with different combinations of BRCA1/BRCA2 test outcomes is presented. Results showed that mixed pairs reported more anger, noted less friendly general support actions, and regarded their sibling to be more dominant and less friendly. The interpersonal strain between siblings with differen test results is investigated.

A maximum-likelihood method to estimate the recombination fraction and its sampling variance using informative and noninformative half-sib offspring is derived. Estimates of the recombination fraction are biased up to 20 cM when noninformative offspring are discarded. In certain scenarios, the sampling variance can be increased or reduced up to fivefold due to the bias in estimating the recombination fraction and the LOD score can be reduced up to 5 units when discarding noninformative offspring. Comparison of the estimates of recombination fraction, map distance, and LOD score when constructing a genetic map with 251 two-point linkage analyses and six families of Norwegian cattle was carried out to evaluate the implications of discarding noninformative offspring in practical situations. The average discrepancies in absolute value (average difference when using and neglecting noninformative offspring) were 0.0146, 1.64 cM, and 2.61 for the recombination fraction, map distance, and the LOD score, respectively. A method for simultaneous estimation of allele frequencies in the dam population and a transmission disequilibrium parameter is proposed. This method might account for the bias in estimating allele frequencies in the dam population when the half-sib offspring is selected for production traits.

The multiallelic sibling disequilibrium test (SDT) can be combined with the multiallelic transmission disequilibrium test (TDT). The component sign test described by Horvath and Laird in their description of the SDT can be extended to incorporate TDT data. A procedure is outlined for employing TDT data from families in which more than one child is affected or for cases in which genotyping is available for only one parent.