Fig 1.
(A) This example of the two-generation family structure has a founding couple with affected children and
total children. (B) This example of the three-generation family structure has a founding couple with
affected children,
total children,
affected grandchildren, and
total grandchildren.
Fig 2.
Proportion carrying HPRV in affected sibships.
The proportion (Ep) of individuals carrying a highly penetrant rare variant (HPRV) in affected sibships for a disease with a 2% prevalence (100 × π*) in the population. Panels A, B, and C represent different values of polygenic heritability (A: , B:
, C:
). Within a panel, the four sets of bars represent different MAF (pG = 0.00001, 0.0001, 0.001, or 0.01; note, the number in parenthesis is the resulting Sibling Relative Risk). Within a set of bars, the colors represent the different number of children (red:
, purple:
, blue:
). See Supporting Information: S2 Fig for diseases with other prevalences.
Fig 3.
Proportion carrying HPRV in multi-generational families.
The proportion (Ep) of individuals carrying a highly penetrant rare variant (HPRV) in affected multi-generational families for a disease with a 2% prevalence (100×π*) in the population. Panels A, B, and C represent different values of polygenic heritability (A: , B:
, C:
). Within a panel, the four sets of bars represent different MAF (pG = 0.00001, 0.0001, 0.001, or 0.01; note, the number in parenthesis is the resulting Sibling Relative Risk). Within a set of bars, the colors represent the different numbers of total affected individuals (red:
, purple:
, blue:
). See Supporting Information: S3 Fig for diseases with other prevalences.
Fig 4.
Enrichment and power to detect HPRV by the PRS statistic.
Panels A and B show the enrichment (M) of HPRV as a function of the PRS statistic for a sibship with four affected individuals and a multi-generational family with six affected individuals. The X-axis is the quantile of the statistic (i.e. 0.1 represents a family at the top 10th percentile). Panels C and D show the power (β) to detect an association with the HPRV when a sibship has four affected individuals and when a multi-generational family has six affected individuals. The X-axis is the quantile of the statistic (i.e. 0.1. represents a study where we select the 10% of affected families with the highest PRS statistic). In all four panels, the color indicates the PRS heritability (red, purple, blue indicates , 0.1, and 0.05 respectively), the MAF is fixed at pG = 0.0001, the polygenic heritability is fixed at
, and the disease prevalence is fixed at 100π* = 2%. See Supporting Information: S4 Fig for other diseases with other prevalences and HPRV MAFs.
Fig 5.
This figure compares the test statistic, Ti, that accounts for PRS and the test statistic, , that does not account for PRS in the 404 families with Melanoma.
Each dot represents one family and red dots indicate families with an HPRV. The spearmen correlation (ρ) between Ti and is 0.92.