Adequacy of the gamma distribution.

<p>The gamma distribution provides an adequate fit for multiple types of pedigrees. For example, HRP UT-549917 has <i>k</i> = 4.4 and <i>σ</i> = 3.6 with good visual density (a) and CDF (b) fit, with <i>λ</i> = 0.9. (Goodness of fit was estimated with <i>λ</i>, the median of empirical chi-squared distribution divided by the median of the expected chi-squared distribution.) HRP UT-34955 has <i>k</i> = 2.8 and <i>σ</i> = 2.9 with good visual density (c) and CDF (d) fit, with <i>λ</i> = 1.0.</p

Significant or overlapping SGSs and segregating SNVs.

<p>Significant or overlapping SGSs and segregating SNVs.</p

Adequacy of the gamma distribution.

<p>The gamma distribution provides an adequate fit for multiple types of pedigrees. For example, HRP UT-549917 has <i>k</i> = 4.4 and <i>σ</i> = 3.6 with good visual density (a) and CDF (b) fit, with <i>λ</i> = 0.9. (Goodness of fit was estimated with <i>λ</i>, the median of empirical chi-squared distribution divided by the median of the expected chi-squared distribution.) HRP UT-34955 has <i>k</i> = 2.8 and <i>σ</i> = 2.9 with good visual density (c) and CDF (d) fit, with <i>λ</i> = 1.0.</p

Genome-wide significance thresholds.

<p>Fitted distributions are stable enough for threshold determination after 100,000 to 300,000 simulations.</p

Significant SGS, pedigrees, and segregating SNVs.

<p>In pedigrees, MM cases are fully shaded and MGUS cases are half shaded. Numbers indicate multiple individuals. a) Utah pedigree, 571744, sharing the genome-wide significant SGS. The pedigree is trimmed to allow for viewing (37 MM confirmed cases are known in this pedigree, 3 were ascertained and genotyped). + indicates the genotyped MM cases that are SGS carriers, − indicates genotyped and non-carriers, no carrier status indicates not genotyped. Note–the genealogy extends beyond SEER cancer registry data. MGUS status is unknown in this pedigree. b) Genomic region of significant SGS. c) INSERM pedigree carrying the stop gain SNV marked by “c” in box e. 1 MM and 2 MGUSs carry the SNV. d) Mayo Clinic pedigree carrying the missense SNV marked by “d” in box e. 1 MM and 1 MGUS carry the SNV, but 2 unaffected siblings do not carry the SNV. e) Risk candidate gene, <i>USP45</i>, has 2 segregating SNVs in the ubiquitin C-terminal hydrolase 2 (UCH) domain.</p

SGS with multiple lines of evidence.

<p>a/b) Utah pedigrees carrying the overlapping SGSs on chr1p36.11-p35.1. + indicates the genotyped MM cases that are SGS carriers, − indicates genotyped and non-carriers, no carrier status indicates not genotyped. c) Weill Cornell pedigree with a segregating, missense SNV in <i>ARID1A</i> indicated by “c” in box e. d) Genomic region of overlapping SGS. Dark black genes fall in both regions. e) 2 rare and segregating, missense SNVs were observed in whole-exome sequencing. SNV “b” is carried by the cases indicated with + in box b. SNV “c” in carried by the cases in box c.</p