G David Poznik | PubMed Health

PubMed2006

A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes.

We performed a variance components linkage analysis of renal function, measured as glomerular filtration rate (GFR), in 63 extended families with multiple members with type 2 diabetes. GFR was estimated from serum concentrations of cystatin C and creatinine in 406 diabetic and 428 nondiabetic relatives. Results for cystatin C were summarized because they are superior to creatinine results. GFR aggregates in families with significant heritability (h(2)) in diabetic (h(2) = 0.45, P < 1 x 10(-5)) and nondiabetic (h(2) = 0.36, P < 1 x 10(-3)) relatives. Genetic correlation (r(G) = 0.35) between the GFR of diabetic and nondiabetic relatives was less than one (P = 0.01), suggesting that genes controlling GFR variation in these groups are different. Linkage results supported this interpretation. In diabetic relatives, linkage was strong on chromosome 2q (logarithm of odds [LOD] = 4.1) and suggestive on 10q (LOD = 3.1) and 18p (LOD = 2.2). In nondiabetic relatives, linkage was suggestive on 3q (LOD = 2.2) and 11p (LOD = 2.1). When diabetic and nondiabetic relatives were combined, strong evidence for linkage was found only on 7p (LOD = 4.0). In conclusion, partially distinct sets of genes control GFR variation in relatives with and without diabetes on chromosome 2q, possibly on 10q and 18p in the former, and on 7p in both. None of these genes overlaps with genes controlling variation in urinary albumin excretion.

Adult↗

PubMed2005

A novel framework for sib pair linkage analysis.

Sib pair linkage analysis of a dichotomous trait is a popular method for narrowing the search for genes that influence complex diseases. Although the pedigree structures are uncomplicated and the underlying genetic principles straightforward, a surprising degree of complexity is involved in implementing a sib pair study and interpreting the results. Ascertainment may be based on affected, discordant, or unaffected sib pairs, as well as on pairs defined by threshold values for quantitative traits, such as extreme discordant sib pairs. To optimize power, various domain restrictions and null hypotheses have been proposed for each of these designs, yielding a wide array of choices for the analyst. To begin, we systematically classify the major sources of discretion in sib pair linkage analysis. Then, we extend the work of Kruglyak and Lander (1995), to bring the various forms into a unified framework and to facilitate a more general approach to the analysis. Finally, we describe a new, freely available computer program, Splat (Sib Pair Linkage Analysis Testing), that can perform any sib pair statistical test currently in use, as well as any user-defined test yet to be proposed. Splat uses the expectation maximization algorithm to calculate maximum-likelihood estimates of sharing (subject to user-specified conditions) and then plots LOD scores versus chromosomal position. It includes a novel grid-scanning capability that enables simultaneous visualization of multiple test statistics. This can lead to further insight into the genetic basis of the disease process under consideration. In addition, phenotype definitions can be modified without the recalculation of inheritance vectors, thereby providing considerable flexibility for exploratory analysis. The application of Splat will be illustrated with data from studies on the genetics of diabetic nephropathy.

Algorithms↗