Fig. 1

Flow chart of analytic strategy. A brief overview of our incremental strategy for finding inherited CNVs contributing to susceptibility of BPD. The flow chart illustrates our hierarchical two-stage selection procedure to reduce the entire wave 1–4 pedigree sample from NIMH Bipolar Disorder Genetic Initiative, into a smaller sample aiming to reduce heterogeneity and increase power to find segregating CNV with risk to BPD. The two screening methods we applied were a genome-wide family-wise linkage analysis and an analysis for the presence of stretches of deletions in BP-candidate genes. Calculation for linkage was performed under 3 different affection status models (ASMs). ASM 1: bipolar type 1 and schizoaffective disorder bipolar type, ASM 2: bipolar type 1 and schizoaffective disorder bipolar type and bipolar type 2, ASM 3: bipolar type 1 and schizoaffective disorder bipolar type and bipolar type 2 and recurrent depressive disorder. These analyses intend to ensure that family members were ascertained for having high genetic liability to BPD. Our selection procedure implies that a subsample of families and family members were selected out of the entire wave1–4 samples. The main features in marker calling for SNPs (using polymorphic markers) and CNVs (monomorphic markers) are shown. The flow chart illustrates the two different analyses that were used to test for inherited CNVs (i) a linkage analysis and (ii) a CNV-weighted linkage analysis which is based on our algorithm that sum the family-wise linkage scores in regions with CNVs that are shared within and across families. We addressed the issue with clinical and genetic heterogeneity for risk to BPD by categorizing individuals into 3 different ASMs and tested for parametric linkage under dominant and recessive models, and for non-parametric (HLOD) linkage